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Amyotrophic Lateral Sclerosis &... Nov 2021
Topics: Amyotrophic Lateral Sclerosis; Azathioprine; Humans
PubMed: 32814467
DOI: 10.1080/21678421.2020.1809821 -
Journal of Clinical Oncology : Official... Dec 2023High hyperdiploidy, the largest and favorable subtype of childhood ALL, exhibits significant biological and prognostic heterogeneity. However, factors contributing to...
PURPOSE
High hyperdiploidy, the largest and favorable subtype of childhood ALL, exhibits significant biological and prognostic heterogeneity. However, factors contributing to the varied treatment response and the optimal definition of hyperdiploidy remain uncertain.
METHODS
We analyzed outcomes of patients treated on two consecutive frontline ALL protocols, using six different definitions of hyperdiploidy: chromosome number 51-67 (Chr51-67); DNA index (DI; DI1.16-1.6); United Kingdom ALL study group low-risk hyperdiploid, either trisomy of chromosomes 17 and 18 or +17 or +18 in the absence of +5 and +20; single trisomy of chromosome 18; double trisomy of chromosomes 4 and 10; and triple trisomy (TT) of chromosomes 4, 10, and 17. Additionally, we characterized ALL ex vivo pharmacotypes across eight main cytotoxic drugs.
RESULTS
Among 1,096 patients analyzed, 915 had B-ALL and 634 had pharmacotyping performed. In univariate analysis, TT emerged as the most favorable criterion for event-free survival (EFS; 10-year EFS, 97.3% 86.8%; = .0003) and cumulative incidence of relapse (CIR; 10-year CIR, 1.4% 8.8%; = .002) compared with the remaining B-ALL. In multivariable analysis, accounting for patient numbers using the akaike information criterion (AIC), DI1.16-1.6 was the most favorable criterion, exhibiting the best AIC for both EFS (hazard ratio [HR], 0.45; 95% CI, 0.23 to 0.88) and CIR (HR, 0.45; 95% CI, 0.21 to 0.99). Hyperdiploidy and subgroups with favorable prognoses exhibited notable sensitivities to asparaginase and mercaptopurine. Specifically, asparaginase sensitivity was associated with trisomy of chromosomes 16 and 17, whereas mercaptopurine sensitivity was linked to gains of chromosomes 14 and 17.
CONCLUSION
Among different definitions of hyperdiploid ALL, DI is optimal based on independent prognostic impact and also the large proportion of low-risk patients identified. Hyperdiploid ALL exhibited particular sensitivities to asparaginase and mercaptopurine, with chromosome-specific associations.
Topics: Humans; Prognosis; Trisomy; Mercaptopurine; Asparaginase; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37729596
DOI: 10.1200/JCO.23.00880 -
Breastfeeding Medicine : the Official... Apr 2020A 35-year-old pregnant woman visited our outpatient clinical questioning the safety of once daily 50 mg mercaptopurine (MP) during pregnancy and lactation, which was...
A 35-year-old pregnant woman visited our outpatient clinical questioning the safety of once daily 50 mg mercaptopurine (MP) during pregnancy and lactation, which was successfully treating her Crohn's disease. We measured MP and its metabolites in plasma and breast milk and found after 4 hours of intake of MP, no MP or its metabolites in breast milk. We concluded that 4 hours after intake of MP, no exposure of the suckling infant to MP and its metabolites was found while being breastfed.
Topics: Adult; Breast Feeding; Crohn Disease; Female; Humans; Infant; Lactation; Mercaptopurine; Milk, Human; Pregnancy
PubMed: 31414890
DOI: 10.1089/bfm.2019.0101 -
Cell Reports. Medicine Aug 2023Azathioprine (AZA) therapy failure, though not the primary cause, contributes to disease relapse and progression in inflammatory bowel disease (IBD). However, the role...
Azathioprine (AZA) therapy failure, though not the primary cause, contributes to disease relapse and progression in inflammatory bowel disease (IBD). However, the role of gut microbiota in AZA therapy failure remains poorly understood. We found a high prevalence of Blautia wexlerae in patients with IBD with AZA therapy failure, associated with shorter disease flare survival time. Colonization of B. wexlerae increased inflammatory macrophages and compromised AZA's therapeutic efficacy in mice with intestinal colitis. B. wexlerae colonization reduced 6-mercaptopurine (6-MP) bioavailability by enhancing selenium-dependent xanthine dehydrogenase (sd-XDH) activity. The enzyme sd-XDH converts 6-MP into its inactive metabolite, 6-thioxanthine (6-TX), thereby impairing its ability to inhibit inflammation in mice. Supplementation with Bacillus (B.) subtilis enriched in hypoxanthine phosphoribosyltransferase (HPRT) effectively mitigated B. wexlerae-induced AZA treatment failure in mice with intestinal colitis. These findings emphasize the need for tailored management strategies based on B. wexlerae levels in patients with IBD.
Topics: Animals; Mice; Mercaptopurine; Azathioprine; Immunosuppressive Agents; Biological Availability; Inflammatory Bowel Diseases; Colitis; Bacteria
PubMed: 37586320
DOI: 10.1016/j.xcrm.2023.101153 -
Zeitschrift Fur Rheumatologie Aug 2020Despite advances in the diagnosis and treatment, the mortality rate of Takayasu arteritis (TAK) is still elevated even today. The diagnosis is often made after a long... (Review)
Review
Despite advances in the diagnosis and treatment, the mortality rate of Takayasu arteritis (TAK) is still elevated even today. The diagnosis is often made after a long time delay and the course of the disease is characterized by progressive structural vascular lesions. Recently, new recommendations for the management of large vessel vasculitis were published by the European League Against Rheumatism (EULAR). For induction of remission oral glucocorticoids (GC) are administered in an initial daily dose of 40-60 mg. As experience has shown that the cumulative GC demand in TAK is high, GC-sparing treatment with moderately potent immunosuppressants, such as methotrexate, azathioprine and mycophenolate mofetil is recommended from the time of initial diagnosis. In cases of a relapsing course, tocilizumab or tumor necrosis factor (TNF)-alpha inhibitors can be used as an additive off-label treatment. If vascular stenoses persist despite supposedly sufficient inflammation control and if these stenoses are symptomatic, vascular surgery or interventional treatment procedures can be indicated. Such revascularization or even surgical procedures for the treatment of aneurysms should be performed during phases of sufficient drug control of the vasculitis. In quite a few patients progressive vascular lesions continue to develop despite clinical and laboratory analytical remission. Due to the poor correlation of clinical symptoms and acute phase markers with the progression of vascular lesions, the distinction between active and inactive diseases is often a challenge in the clinical practice. Imaging studies can then support therapeutic decisions but are not yet formally and comprehensively validated in the long-term course of TAK.
Topics: Azathioprine; Glucocorticoids; Humans; Immunosuppressive Agents; Methotrexate; Remission Induction; Takayasu Arteritis
PubMed: 32430564
DOI: 10.1007/s00393-020-00806-2 -
BMJ Case Reports Feb 2024Sweet's syndrome is an acute febrile neutrophilic dermatosis. Drug-induced Sweet's syndrome typically occurs soon after drug administration, with rapid resolution of...
Sweet's syndrome is an acute febrile neutrophilic dermatosis. Drug-induced Sweet's syndrome typically occurs soon after drug administration, with rapid resolution of symptoms with cessation of the offending agent. We report a man in his early 40s who presented with fever and widespread erythematous rash on a background of recently diagnosed mild stricturing ileal Crohn's disease. He was commenced on 6-mercaptopurine 12 days before presentation. Skin biopsy demonstrated diffuse infiltration of neutrophils in the upper dermis, dermal oedema, eosinophils and fibrin deposition. Symptoms rapidly improved with cessation of 6-mercaptopurine without requiring systemic corticosteroids.
Topics: Male; Humans; Sweet Syndrome; Mercaptopurine; Skin; Adrenal Cortex Hormones; Crohn Disease
PubMed: 38417937
DOI: 10.1136/bcr-2023-259278 -
Saudi Journal of Gastroenterology :... 2022Methotrexate is an antineoplastic agent that is also used at lower doses for anti-inflammatory properties. Along with thiopurines (azathioprine and 6-mercaptopurine), it... (Review)
Review
Methotrexate is an antineoplastic agent that is also used at lower doses for anti-inflammatory properties. Along with thiopurines (azathioprine and 6-mercaptopurine), it has historically been an important part of pharmacological treatment for patients with inflammatory bowel disease. Despite an increase in therapeutic options, these immunomodulators continue to play important roles in the management of inflammatory bowel disease, used either as a monotherapy in mild to moderate cases or in combination with monoclonal antibodies to prevent immunogenicity and maintain efficacy. In light of data linking the use of thiopurines with the risk of malignancies, methotrexate has regained attention as a potential alternative. In this article, we review data on the pharmacology, safety, and efficacy of methotrexate and discuss options for the positioning of methotrexate alone, or in combination, in therapeutic algorithms for Crohn's disease and ulcerative colitis.
Topics: Azathioprine; Colitis, Ulcerative; Gastroenterologists; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate
PubMed: 35042318
DOI: 10.4103/sjg.sjg_496_21 -
Journal of Crohn's & Colitis Aug 2022Exactly 70 years ago [1951] mercaptopurine was discovered by Gertrude Elion as a novel treatment option for acute leukaemia. A total of three thiopurines (also...
Exactly 70 years ago [1951] mercaptopurine was discovered by Gertrude Elion as a novel treatment option for acute leukaemia. A total of three thiopurines (also thioguanine [1950] and azathioprine [1957]) were developed over time. These immunosuppressive drugs were also successfully introduced a few decades later to prevent rejection of transplanted organs and to treat several autoimmune diseases. For her discovery of thiopurines and other antimetabolite drugs, in 1988 Elion was rewarded, together with George Hitchings and James Black, with the Nobel Prize in Physiology or Medicine. Important steps have been made in recent years to unravel its metabolism, mode of action and pharmacogenetics. Today thiopurine [based] therapy remains an essential immunosuppressive approach in treating patients with inflammatory bowel disease.
Topics: Antimetabolites; Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Thioguanine
PubMed: 35024806
DOI: 10.1093/ecco-jcc/jjac004 -
Clinical Gastroenterology and... Oct 2023The aim of this study was to assess how 6-thioguanine nucleotide (6-TGN) levels and use of oral methotrexate relate to the pharmacokinetics of biologics.
BACKGROUND AND AIMS
The aim of this study was to assess how 6-thioguanine nucleotide (6-TGN) levels and use of oral methotrexate relate to the pharmacokinetics of biologics.
METHODS
This was a prospective cohort study including patients with inflammatory bowel diseases on maintenance doses of infliximab, vedolizumab, or ustekinumab on monotherapy or combination with a thiopurine or oral methotrexate. We collected 6-TGN concentrations, biomarker levels, and clinical and endoscopic disease activity. The primary outcomes were infliximab, vedolizumab, and ustekinumab concentrations as well as anti-drug antibodies (ADAs).
RESULTS
A total of 369 patients were recruited (113 infliximab, 133 vedolizumab, and 123 ustekinumab). Patients with 6-TGN levels ≥146 pmol per 8 × 10 red blood cells (RBCs), and those receiving combination therapy with thiopurine or oral methotrexate had significantly higher infliximab concentrations when compared with monotherapy (median levels of 17.4 μg/mL on thiopurine with 6-TGN ≥146 pmol per 8 × 10 RBCs, 17.1 on methotrexate, and 3.9 on infliximab monotherapy; P = .001 for both comparisons). However, there was no association between the use of immunomodulators and 6-TGN concentrations with vedolizumab (median levels of 8.8 on thiopurine with 6-TGN ≥152 pmol per 8 × 10 RBCs, 6.8 on methotrexate, and 10.5 on vedolizumab monotherapy; P > .05 for both comparisons) or ustekinumab median concentrations (median levels of 5.0 on thiopurine with 6-TGN ≥154 pmol per 8 × 10 RBCs, 5.2 on methotrexate and 7.0 on ustekinumab monotherapy; P > .05 for both comparisons). Fourteen (12%) patients had anti-infliximab antibodies, while 1 patient had ADAs in each of the other drug cohorts.
CONCLUSIONS
Achieving higher 6-TGN levels or the use of methotrexate improved the pharmacokinetics of infliximab. Conversely, these data do not support the use of combination therapy to augment pharmacokinetics with vedolizumab or ustekinumab.
Topics: Humans; Infliximab; Azathioprine; Ustekinumab; Mercaptopurine; Methotrexate; Prospective Studies; Immunologic Factors; Antibodies, Monoclonal, Humanized; Inflammatory Bowel Diseases; Immunosuppressive Agents
PubMed: 36280102
DOI: 10.1016/j.cgh.2022.10.016 -
Expert Opinion on Drug Metabolism &... Oct 2021Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurines (mercaptopurine (MP) and tioguanine (TG)), chemotherapeutic agents used in the treatment... (Review)
Review
INTRODUCTION
Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurines (mercaptopurine (MP) and tioguanine (TG)), chemotherapeutic agents used in the treatment of acute lymphoblastic leukemia (ALL). Polymorphisms in gene encode diminished activity enzyme, enhancing accumulation of active metabolites, and partially explaining the inter-individual differences in patients' clinical response.
AREAS COVERED
This review gives an overview on gene and function, and discusses the pharmacogenomic implications of variants in the prevention of severe thiopurine-induced hematological toxicities and the less known implication on TG-induced sinusoidal obstruction syndrome. Additional genetic and non-genetic factors impairing TPMT activity are considered. Literature search was done in PubMed for English articles published since1990, and on PharmGKB.
EXPERT OPINION
To titrate thiopurines safely and effectively, achieve the right degree of lymphotoxic effect and avoid excessive myelosuppression, the optimal management will combine a preemptive genotyping to establish a safe initial dose with a close phenotypic monitoring of TPMT activity and/or of active metabolites during long-term treatment. Compared to current ALL protocols, replacement of TG by MP during reinduction phase in heterozygotes and novel individualized TG regimens in maintenance for subjects could be investigated to improve outcomes while avoiding risk of severe hepatotoxicity.
Topics: Animals; Antimetabolites, Antineoplastic; Genotype; Humans; Mercaptopurine; Methyltransferases; Molecular Targeted Therapy; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine
PubMed: 34452592
DOI: 10.1080/17425255.2021.1974398