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European Journal of Internal Medicine Jul 2020Virus-negative or autoimmune myocarditis(VNM) is an inflammatory disease affecting the myocardium that may occur as a distinct disease with exclusive cardiac... (Review)
Review
Virus-negative or autoimmune myocarditis(VNM) is an inflammatory disease affecting the myocardium that may occur as a distinct disease with exclusive cardiac involvement, or in the context of systemic autoimmune or inflammatory disorders. The pathogenesis of VNM involves both innate and acquired immunity and is not completely elucidated: an early immune-mediated pathogenic process lead to subacute and chronic stages and eventually results in tissue remodeling, fibrosis, contractile dysfunction, dilated cardiomyopathy and arrhythmic burden, accounting for a dismal prognosis. Treatment interventions effectively curbing the acute inflammatory process at an early stage can prevent late cardiac remodeling and improve patient's outcome. The mainstay of treatment of VNM remains symptomatic therapy of heart failure and arrhythmia, while the use of immunosuppressive treatments has long been considered controversial until recently, and strategies effectively targeting the inflammatory and immune-mediated substrate of the disease remain elusive. Only steroids and azathioprine have been tested in clinical trials, and nowadays represent the therapy of choice. A substantial proportion of patients are resistant to first line strategies, suggesting that some critical inflammatory mechanisms are not responsive to conventional immunosuppression with steroids and azathioprine, or experience drug-related adverse events. Thus, second-line targeted therapeutic strategies to treat VNM are eagerly awaited. Recent data on the pathogenic mechanisms underlying myocardial inflammation are paving the way to novel, promising treatment strategies for myocarditis, which could reformulate future treatment strategies for VNM. In this review, we summarize the current therapeutic opportunities, beyond corticosteroids, to treat VNM, including conventional and biologic immunosuppressive drugs and cytokine blocking agents.
Topics: Azathioprine; Cardiomyopathy, Dilated; Humans; Immunosuppressive Agents; Myocarditis; Myocardium
PubMed: 32402564
DOI: 10.1016/j.ejim.2020.04.050 -
Journal of Oncology Pharmacy Practice :... Dec 2023Vincristine is a vesicant chemotherapeutic agent which may leak from the vessel at the infusion site to the perivascular tissue and cause extravasation. Extravasation, a...
INTRODUCTION
Vincristine is a vesicant chemotherapeutic agent which may leak from the vessel at the infusion site to the perivascular tissue and cause extravasation. Extravasation, a severe complication of chemotherapeutic drugs, can result in tissue necrosis that is considered an oncological emergency.
CASE REPORT
We aimed to report a case of a 29-year-old woman with ALL-B cell (Acute lymphoblastic leukemia) on maintenance chemotherapy regimen including vincristine, methotrexate, prednisolone, and 6-mercaptopurine (POMP). 48 h after administering intravenous vincristine, the patient experienced burning, pain and tenderness at the injection site (left hand - cubital cavity).
MANAGEMENT & OUTCOME
7 days after the onset of symptoms, the patient was hospitalized with a large brown lesion at the site. She was prescribed betamethasone cream, DSMO (Dimethyl sulfoxide) solution, and oral levofloxacin on his second day after admission. The lesion was completely improved 10 days after initiation of therapy and there were no serious problems.
DISCUSSION
Due to the ineffectiveness of antidote therapy for the management of delayed extravasation of vincristine and beneficial effect of our clinical approach, it could consider for the management of similar cases with delayed extravasation following vincristine administration.
Topics: Female; Humans; Adult; Vincristine; Antineoplastic Combined Chemotherapy Protocols; Methotrexate; Mercaptopurine; Prednisolone
PubMed: 37475540
DOI: 10.1177/10781552231187591 -
Pediatric Research Jan 2021Mercaptopurine-induced neutropenia can interrupt chemotherapy and expose patients to infection during childhood acute lymphoblastic leukemia (ALL) treatment. Previously,...
BACKGROUND
Mercaptopurine-induced neutropenia can interrupt chemotherapy and expose patients to infection during childhood acute lymphoblastic leukemia (ALL) treatment. Previously, six candidate gene variants associated with mercaptopurine intolerance were reported. Herein, we investigated the association between the mean tolerable dose of mercaptopurine and these genetic variants in Taiwanese patients.
METHODS
In total, 294 children with ALL were treated at the National Taiwan University Hospital from April 1997 to December 2017. Germline variants were analyzed for NUDT15, SUCLA2, TPMT, ITPA, PACSIN2, and MRP4. Mean daily tolerable doses of mercaptopurine in the continuation phase of treatment were correlated with these genetic variants.
RESULTS
Mercaptopurine intolerance was significantly associated with polymorphisms in NUDT15 (P value < 0.0001). Patients with SUCLA2 variants received lower mercaptopurine doses (P value = 0.0119). The mean mercaptopurine doses did not differ among patients with TPMT, ITPA, MRP4, and PACSIN2 polymorphisms (P value = 0.9461, 0.5818, and 0.7951, respectively). After multivariable linear regression analysis, only NUDT15 variants retained their clinically significant correlation with mercaptopurine intolerance (P value < 0.0001).
CONCLUSION
In this cohort, the major genetic determinant of mercaptopurine intolerance was NUDT15 in Taiwanese patients.
IMPACT
NUDT15 causes mercaptopurine intolerance in children with ALL. The NUDT15 variant is a stronger predictor of mercaptopurine intolerance than TPMT in a Taiwanese cohort. This finding is similar with studies performed on Asian populations rather than Caucasians. Pre-emptive genotyping of the patients' NUDT15 before administering mercaptopurine may be more helpful than genotyping TPMT in Asians.
Topics: Antimetabolites, Antineoplastic; Humans; Mercaptopurine; Methyltransferases; Neutropenia; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases; Retrospective Studies; Risk Assessment; Risk Factors; Taiwan
PubMed: 32221476
DOI: 10.1038/s41390-020-0868-8 -
Alimentary Pharmacology & Therapeutics Jun 2020Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve... (Review)
Review
BACKGROUND
Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use.
AIMS
To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response.
METHODS
English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed.
RESULTS
Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance.
CONCLUSIONS
The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.
Topics: Allopurinol; Azathioprine; Drug-Related Side Effects and Adverse Reactions; Guanine Nucleotides; Hepatitis, Autoimmune; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Purines; Quality Improvement; Thioguanine; Thionucleotides; Treatment Outcome
PubMed: 32363674
DOI: 10.1111/apt.15743 -
Skinmed 2022Anagen effluvium and myelosuppression are rare adverse effects of azathioprine. Hair loss due to azathioprine is more frequent in transplant than in nontransplant...
Anagen effluvium and myelosuppression are rare adverse effects of azathioprine. Hair loss due to azathioprine is more frequent in transplant than in nontransplant patients. We report three patients with azathioprine-induced anagen effluvium and myelosuppression, who were prescribed azathioprine for dermatologic conditions. (. 2022;20:192-196).
Topics: Alopecia Areata; Azathioprine; Humans
PubMed: 35779024
DOI: No ID Found -
World Journal of Gastroenterology Oct 2021Thiopurines are immunomodulators used in the treatment of acute lymphoblastic leukemia and inflammatory bowel diseases. Adverse reactions to these agents are one of the...
Thiopurines are immunomodulators used in the treatment of acute lymphoblastic leukemia and inflammatory bowel diseases. Adverse reactions to these agents are one of the main causes of treatment discontinuation or interruption. Myelosuppression is the most frequent adverse effect; however, approximately 5%-20% of patients develop gastrointestinal toxicity. The identification of biomarkers able to prevent and/or monitor these adverse reactions would be useful for clinicians for the proactive management of long-term thiopurine therapy. In this editorial, we discuss evidence supporting the use of , , and genes, in addition to and as possible biomarkers for thiopurine-related gastrointestinal toxicity.
Topics: Azathioprine; Biomarkers; Humans; Immunologic Factors; Mercaptopurine; Methyltransferases; Pyrophosphatases
PubMed: 34720526
DOI: 10.3748/wjg.v27.i38.6348 -
Frontiers in Immunology 2023Neuromyelitis optica spectrum disorder (NMOSD) is a demyelinating syndrome of the central nervous system. A tremendous amount of literature on NMOSD has been published....
BACKGROUND
Neuromyelitis optica spectrum disorder (NMOSD) is a demyelinating syndrome of the central nervous system. A tremendous amount of literature on NMOSD has been published. This study aimed to perform a bibliometric analysis of the publications on NMOSD and show its hotspots and development trends.
METHODS
We used the Web of Science Core Collection as a database and searched the literature published between 2002 and 2022. CiteSpace, VOSviewer, online bibliometric platform, and R-bibliometrix were used to conduct bibliometric analysis and network visualization, including the number of publications, citations, countries/regions, institutions, journals, authors, references, and keywords.
RESULTS
A total of 3,057 publications on NMOSD were published in 198 journals by 200 authors at 200 institutions from 93 countries/regions. The United States published the most literature and made great contributions to this field. The Mayo Clinic was the institution with the largest number of publications. The journal with the most publications was , and the most co-cited journal was . The author with the most publications was Fujihara, K., while the most frequently co-cited author was Wingerchuk, DM. The current research hotspots may be focused on "efficacy," "multicenter," "interleukin-6 receptor blockade," "safety," "azathioprine," "tolerance," and "adult".
CONCLUSION
This study was the first bibliometric analysis of publications on the NMOSD field, visualizing its bibliometric characteristics and gaining insight into the direction, hotspots, and development of global NMOSD research, which may provide helpful information for researchers. Future research hotspots might be conducting randomized controlled trials on targeted immunotherapy in the NMOSD field.
Topics: Humans; Neuromyelitis Optica; Central Nervous System; Azathioprine; Bibliometrics; Databases, Factual
PubMed: 37346048
DOI: 10.3389/fimmu.2023.1177127 -
Journal of Hepatology Apr 2024
Topics: Humans; Hepatitis, Autoimmune; Immunosuppressive Agents; Azathioprine
PubMed: 38309440
DOI: 10.1016/j.jhep.2024.01.021 -
Pharmacogenomics Jun 20236-mercaptopurine usage is associated with myelotoxicity and increased risk in patients carrying metabolism-related genetic variations. This study aimed to determine the...
6-mercaptopurine usage is associated with myelotoxicity and increased risk in patients carrying metabolism-related genetic variations. This study aimed to determine the frequency of candidate gene polymorphisms and their association with 6-mercaptopurine intolerance. A total of 41 patients on acute lymphoblastic leukaemia treatment were genotyped for and (rs116855232) alleles, and their association with dose intensity was analyzed. The defective allele frequency was 9.8%. The median maintenance dose intensity for participants was considerably lower (47%) when compared with the wild-type (77%), although not statistically significant. This is the first pharmacogenetics study carried out in a black Zimbabwean leukemia patient cohort. The high defective (9.8%) allele frequency points to the potential utility of pharmacogenetics testing for safe usage of 6-mercaptopurine in this population.
Topics: Humans; Mercaptopurine; Pharmacogenetics; Zimbabwe; Antimetabolites, Antineoplastic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Methyltransferases; Pyrophosphatases
PubMed: 37248698
DOI: 10.2217/pgs-2023-0026 -
International Immunopharmacology Oct 2023Inflammasome has been reported to play an important role in the pathogenesis and progression of hematologic malignancies. As one of the backbone drugs for treating acute...
BACKGROUND
Inflammasome has been reported to play an important role in the pathogenesis and progression of hematologic malignancies. As one of the backbone drugs for treating acute lymphoblastic leukemia (ALL), the anti-inflammatory effect of mercaptopurine (6-MP) and the impact of gut microbiome changes caused by 6-MP on anti-inflammasome remain unclear.
OBJECTIVE
We aimed to explore the association between 6-MP therapeutic effects and microbiome-involved inflammatory responses in ALL mice models.
STUDY DESIGN
ALL murine model was built by i.v. injecting murine L1210 cells into DBA/2 mice (model group). Two weeks after cell injections, 6-MP was orally administrated for 14 days (6-MP group). Fecal samples of mice were collected at different time points. Cecum short-chain fatty acids (SCFAs) concentrations were determined by LC-MS/MS method. Serum cytokines were measured using a cytometric bead array. Gut microbiota composition in mice was explored using 16S rRNA gene sequencing.
RESULTS
The anti-tumor effect of 6-MP was proved in ALL mice models. The levels of pro-inflammatory factors IL-6 and TNFα significantly decreased after the administration of 6-MP. Cecum contents' acetate, propionate, and butyrate levels were negatively correlated with IL-6 (correlation coefficient: acetate, -0.24; propionate, -0.26; butyrate, -0.17) and TNFα (correlation coefficient: acetate, -0.45; propionate, -0.42; butyrate, -0.31) changes. Relative abundance changes of f_Lachnospiraceae.g_ASF356 and f_Peptococcaceae.g_uncultured were in accordance with the changes of butyrate levels and opposite to the changes of pro-inflammatory levels.
CONCLUSION
The anti-inflammatory response of 6-MP influenced by intestinal microbiota and its metabolites SCFAs, especially butyrate, played an essential role in improving ALL progression.
Topics: Mice; Animals; Propionates; Tumor Necrosis Factor-alpha; Mercaptopurine; Interleukin-6; RNA, Ribosomal, 16S; Chromatography, Liquid; Mice, Inbred DBA; Tandem Mass Spectrometry; Fatty Acids, Volatile; Microbiota; Butyrates; Acetates; Anti-Inflammatory Agents; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37573688
DOI: 10.1016/j.intimp.2023.110782