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European Journal of Clinical... Mar 2019The thiopurines azathioprine and 6-mercaptopurine are frequently used for remission maintenance in patients with inflammatory bowel diseases. However, there are therapy...
PURPOSE
The thiopurines azathioprine and 6-mercaptopurine are frequently used for remission maintenance in patients with inflammatory bowel diseases. However, there are therapy failures, and it is unclear whether clinical and laboratory parameters can be used to predict thiopurine metabolite concentrations (as a surrogate for adequate remission maintenance therapy) and clinical outcome in these patients.
METHODS
In this retrospective analysis of clinical routine patient data, multivariate statistical models based on Linear Mixed Models regression and Generalized Estimating Equations logistic regression were developed. The adequacy of the models was assessed using Pearson's correlation and a receiver operating characteristic curve.
RESULTS
This study included 273 patients and 1158 thiopurine metabolite measurements as well as routine laboratory and clinical data. In the statistical models, thiopurine metabolite concentrations and the odds of non-remission based on different clinical and laboratory parameters were computed. Correlation (r) between predicted and measured thiopurine metabolites were 0.40 (p < 0.001) for 6-thioguanine nucleotides and 0.53 (p < 0.001) for 6-methyl-mercaptopurine nucleotides, respectively. The model for remission classified data sets in remission and non-remission with a sensitivity of 63% and a specificity of 73%. The area under the receiver operating characteristic curve of the model was 0.72.
CONCLUSIONS
Although the models are not yet accurate enough to be used in clinical routine, model-based prediction of thiopurine metabolite concentrations and of outcome is feasible. Until more accurate models are developed and validated, traditional therapeutic drug monitoring of thiopurine metabolites in patients with inflammatory bowel diseases under thiopurine therapy stays the best tool to individualize therapy.
Topics: Adult; Area Under Curve; Azathioprine; Drug Monitoring; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Models, Statistical; Predictive Value of Tests; Retrospective Studies; Treatment Outcome
PubMed: 30610277
DOI: 10.1007/s00228-018-02616-7 -
Inflammatory Bowel Diseases Feb 2012Thiopurines are considered immunosuppressive agents and may be associated with an increased risk for infections. However, few inflammatory bowel disease (IBD) patients...
BACKGROUND
Thiopurines are considered immunosuppressive agents and may be associated with an increased risk for infections. However, few inflammatory bowel disease (IBD) patients are appropriately vaccinated, and data on their ability to mount an immune response are vague. We evaluated the effects of the thiopurines, azathioprine (AZA) and 6-mercaptopurine (6-MP), on cellular and humoral immune responses in IBD patients.
METHODS
A prospective clinical investigation was conducted on IBD patients referred for thiopurine treatment. Immune competence was evaluated by assessing lymphocyte counts and phenotype, response to mitogen and antigen stimulation, immunoglobulin levels, and response to pneumococcal and tetanus vaccines (before treatment, week 0), and to Haemophilus influenza type b vaccine (at week 24).
RESULTS
Thirty-one Crohn's disease and 12 ulcerative colitis patients who completed at least 24 weeks of therapy were included. The posttherapy average 6-MP dose was 1.05 ± 0.30 mg/kg, and white blood cell counts had decreased significantly from baseline values (P < 0.002). The posttreatment response to mitogens and antigens and the immunoglobulin levels were unchanged. Responses to vaccines were normal both in thiopurine-naïve and thiopurine-treated patients, suggesting that these patients were immunologically intact while on thiopurine therapy and capable of generating normal immune responses in vivo.
CONCLUSIONS
There is no evidence for any intrinsic systemic immunodeficiency in IBD patients. Thiopurines at the doses used for treating IBD showed no significant suppressive effect on the systemic cellular and humoral immune responses evaluated. Thiopurine-treated IBD patients can be safely and efficiently vaccinated.
Topics: Adult; Azathioprine; Female; Gastrointestinal Agents; Humans; Immune Tolerance; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukocyte Count; Male; Mercaptopurine; Middle Aged; Vaccines; Young Adult
PubMed: 21438101
DOI: 10.1002/ibd.21688 -
Alimentary Pharmacology & Therapeutics Jul 2004Forty per cent of patients with inflammatory bowel disease fail to respond to standard dose azathioprine (2 mg/kg/day).
BACKGROUND
Forty per cent of patients with inflammatory bowel disease fail to respond to standard dose azathioprine (2 mg/kg/day).
AIMS
To evaluate the efficacy and safety of increasing the azathioprine dose according to a fixed schedule and guided by clinical response and adverse effects.
METHODS
We reviewed the records of all patients with inflammatory bowel disease treated by a single clinician over 6 years, unresponsive to at least 3 months treatment with standard dose azathioprine, and whose dose was subsequently increased.
RESULTS
Forty patients (27 male; 24 Crohn's, 16 ulcerative colitis) with chronic active disease or recurrent flares despite standard dose azathioprine for a median 8 months (range 3-114) increased their dose from a median 2.02 (1.61-3.19) mg/kg/day to 2.72 (2.37-3.99) mg/kg/day in one to four increments of 0.5 mg/kg/day, and were followed over a median 6 (0.5-54) months. Eleven of the 40 patients (seven Crohn's, four ulcerative colitis) responded or had reduced frequency of flare-ups at the end of follow-up, while 17 of the 40 patients had no benefit. Response was more likely for maximum doses < or =2.5 mg/kg/day (six of 11 patients) than for doses >2.5 mg/kg/day (five of 29 patients) (P = 0.042). Twelve patients (11 of whom received maximum doses >2.5 mg/kg/day) were unable to maintain an increased azathioprine dose because of leukopenia in eight, nausea in three, and raised liver enzymes in one (all transient and reversible).
CONCLUSIONS
Increasing the azathioprine dose up to 2.5 mg/kg/day appears beneficial in patients who have not responded to 2 mg/kg/day. Further increase above 2.5 mg/kg/day is less likely to be efficacious, and is associated with a substantial risk of adverse reactions.
Topics: Adult; Azathioprine; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Drug Evaluation; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Retrospective Studies; Treatment Outcome
PubMed: 15225172
DOI: 10.1111/j.1365-2036.2004.02009.x -
BMC Microbiology Mar 2023Autophagy is an important part of pathogenesis of IBD. Thiopurines such as azathioprine (AZA) are approved drugs for clinical practices in IBD patients. Besides, as an...
BACKGROUND
Autophagy is an important part of pathogenesis of IBD. Thiopurines such as azathioprine (AZA) are approved drugs for clinical practices in IBD patients. Besides, as an escape strategy, Toxoplasma gondii can use the mTORC1 complex to inactivate autophagy.
METHODS
In this study, we investigated whether T. gondii tachyzoites may modulate autophagy and interfere the effects of azathioprine in IBD treatment. PMA-activated human monocyte cell line (THP-1) was infected with fresh T. gondii RH tachyzoites. After 5 h of infection, the cells were treated with AZA for 6 h. The expression of atg5, atg7, atg12, lc3b, and β-actin (BACT) genes was evaluated using quantitative real-time PCR. To analyze the phosphorylation of ribosomal protein S6 (rpS6), western blot using specific primary antibodies was performed.
RESULTS
The results of real-time PCR revealed that AZA, T. gondii tachyzoites, and a combination of AZA and T. gondii tachyzoites upregulated atg5 gene for 4.297-fold (P-value = 0.014), 2.49-fold (P-value = 0.006), and 4.76-fold (P-value = 0.001), respectively. The atg7 gene showed significant upregulation (2.272-fold; P-value = 0.014) and (1.51-fold; P-value = 0.020) in AZA and AZA / T. gondii, respectively. The expression of atg12 gene was significantly downregulated in AZA and T. gondii tachyzoites for (8.85-fold; P-value = 0.004) and (2.005-fold; P-value = 0.038), respectively, but upregulated in T. gondii/AZA (1.52-fold; P-value = 0.037). In addition, the lc3b gene was only significantly changed in AZA / T. gondii (3.028-fold; P-value = 0.001). Western blot analysis showed that T. gondii tachyzoites significantly phosphorylated rpS6, and tachyzoites did not interfere the effects of AZA to phosphorylate the rpS6.
CONCLUSION
Taken together, although AZA and T. gondii similarly affects the expression levels of atg5, atg7, and atg12, but T. gondii does not seem to modulate the effects of AZA via mTORC functions.
Topics: Humans; Toxoplasma; Azathioprine; Monocytes; Cell Line; Inflammatory Bowel Diseases
PubMed: 36941573
DOI: 10.1186/s12866-023-02819-8 -
Journal of Ayub Medical College,... 2022Azathioprine is first line immunosuppressive agent in treatment of chronic actinic dermatitis. The role of methotrexate has been effective in different dermatosis and it... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Azathioprine is first line immunosuppressive agent in treatment of chronic actinic dermatitis. The role of methotrexate has been effective in different dermatosis and it seems reasonable to use it in the treatment of chronic actinic dermatitis.
AIMS
We sought to compare the efficacy of methotrexate versus azathioprine in treatment of chronic actinic dermatitis.
METHODS
Patients with chronic actinic dermatitis were randomized to receive methotrexate in group A and azathioprine in group B. The response to treatment in terms of percentage PASI reduction and side effects of medications were assessed 12 weeks follow-up.
RESULTS
In group A, the percentage PASI reduction was <25% in 2 (1.19%) patients, 25-49% in 47 (27.9%) patients, 50-74% was achieved by 35 (20.8%) patients while in group B, the percentage PASI reduction of 25% was achieved by 2 (1.19%) patients, 25-49% in 45 (26.7%) patients, 50-74% in 37 (22.0%) patients. More than or equal to 75 percentage PASI reduction was not achieved by any patient in the study. Both drugs were found efficacious in treatment of CAD. A total of 23 (27.38%) patients in group A and 22 (26.19%) patients in group B showed derangement in laboratory investigations during 12 weeks treatment. The limitation of study was inability to do photo-patch test, so patients were diagnosed clinically and biopsy was done in clinically challenging cases.
CONCLUSION
: This study shows that methotrexate is equally effective as azathioprine in the treatment of chronic actinic dermatitis with its added benefits of being cost effective and better safety profile.
Topics: Humans; Azathioprine; Methotrexate; Photosensitivity Disorders; Immunosuppressive Agents; Treatment Outcome
PubMed: 36414584
DOI: 10.55519/JAMC-03-S1-9643 -
Value in Health Regional Issues Mar 2022Azathioprine has been the therapy of choice for the maintenance of remission in patients with antineutrophil cytoplasm antibody (ANCA)-associated systemic vasculitis,...
Cost-Effectiveness of Rituximab (Fixed Schedule vs Tailored Dose) Compared With Azathioprine Maintenance Therapy in Adults With Generalized Antineutrophil Cytoplasm Antibody-Associated Vasculitis in Colombia.
OBJECTIVES
Azathioprine has been the therapy of choice for the maintenance of remission in patients with antineutrophil cytoplasm antibody (ANCA)-associated systemic vasculitis, but recent studies show that rituximab could be more effective. To evaluate the cost-effectiveness of azathioprine, fixed-schedule rituximab, and tailored-dose rituximab for ANCA-associated systemic vasculitis.
METHODS
A Markov model from the perspective of the Colombian healthcare system was designed with annual cycles and a 5-year time horizon, charting the following states: remission, minor relapse, major relapse, and death. The discount rate was 5%. Transition probabilities were obtained from a systematic literature review. The costs (1 US dollar = 2956 Colombian pesos in 2018) were estimated based on national drug registries and official fee manuals for procedures, along with other resources. The main outcomes were quality-adjusted life-years (QALYs) taken from the Tufts registry. Univariate and multivariate sensitivity analyses were performed.
RESULTS
Final costs were $1446 for azathioprine, $4898 for tailored-dose rituximab, and $6311 for fixed-schedule rituximab. QALYs gained were 3.18, 4.08, and 3.98, respectively. Rituximab was cost-effective (cost per incremental QALY gained: $4919, and $6865), and tailored-dose administration had a lower cost. Sensitivity analyses did not affect the results.
CONCLUSIONS
Tailored-dose rituximab was the most cost-effective treatment for ANCA-associated vasculitis. Azathioprine presented worse effectiveness and lower cost, and fixed-schedule rituximab was dominated by tailored-dose rituximab.
Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Azathioprine; Colombia; Cost-Benefit Analysis; Cytoplasm; Humans; Rituximab
PubMed: 34922060
DOI: 10.1016/j.vhri.2021.08.002 -
The New England Journal of Medicine Oct 1995In most patients with autoimmune hepatitis, remission can be maintained with prednisolone, usually in combination with azathioprine, but the majority of patients have a... (Clinical Trial)
Clinical Trial
BACKGROUND
In most patients with autoimmune hepatitis, remission can be maintained with prednisolone, usually in combination with azathioprine, but the majority of patients have a relapse when treatment is stopped and therefore require long-term therapy. Because prolonged corticosteroid therapy may have serious toxic effects, in 1984 we undertook a controlled trial of maintenance therapy with azathioprine alone. None of the 25 patients in that trial had relapses during the follow-up period of one year. We have now followed these 25 patients for 10 years and have treated an additional 47 patients in a similar manner.
METHODS
The 72 patients (median age, 47 years; range, 14 to 71) had been in complete remission for at least one year with 5 to 15 mg of prednisolone per day and 1 mg of azathioprine per kilogram per day. The dose of azathioprine was increased to 2 mg per kilogram per day, and the prednisolone was gradually withdrawn. Remission was defined as the absence of symptoms suggestive of a relapse and serum globulin and aspartate aminotransferase concentrations within the normal range, with or without a liver biopsy showing only minimal inflammation.
RESULTS
Sixty patients (83 percent) remained in remission while receiving azathioprine alone for a median of 67 months (range, 12 to 128). Of 48 follow-up liver biopsies in 42 patients, 45 showed inactive or minimal disease, and 3 showed moderate disease (2 after one year of therapy and 1 after eight years). After the prednisolone had been withdrawn, 26 patients lost their cushingoid facies, and 32 patients lost weight (median loss, 6.4 kg; range, 1.5 to 22.3). The most common adverse effect was arthralgia (in 38 patients). With the higher dose of azathioprine, four patients had myelosuppression, defined as a decrease in the leukocyte and platelet counts to less than 4000 and 150,000 per cubic millimeter, respectively. Two of these patients (both with pancytopenia) relapsed when the azathioprine was withdrawn; in the other two, remission was maintained with the resumption of prednisolone. Lymphopenia developed in 32 of 56 patients treated with 2 mg of azathioprine per kilogram per day for more than two years. During follow-up, nine patients died: one of liver failure and eight of causes not directly related to their liver disease.
CONCLUSIONS
Many patients with autoimmune hepatitis who have been in complete remission for at least one year with prednisolone and azathioprine can remain in remission with a higher dose of azathioprine alone.
Topics: Adolescent; Adult; Aged; Arthralgia; Autoimmune Diseases; Azathioprine; Disease-Free Survival; Female; Follow-Up Studies; Hepatitis; Humans; Leukocyte Count; Male; Middle Aged; Platelet Count; Prednisolone; Recurrence; Substance Withdrawal Syndrome; Treatment Outcome
PubMed: 7666914
DOI: 10.1056/NEJM199510123331502 -
Pediatric Nephrology (Berlin, Germany) Oct 2023Kidney transplantation in children in 1970 was considered by many to be unethical, as long-term survival was minimal. It was therefore risky at the time to offer...
BACKGROUND
Kidney transplantation in children in 1970 was considered by many to be unethical, as long-term survival was minimal. It was therefore risky at the time to offer transplantation to a child.
CASE DIAGNOSIS/TREATMENT
A 6-year-old boy with kidney failure due to haemolytic uraemic syndrome received 4 months of intermittent peritoneal dialysis followed by 6 months of haemodialysis until at 6 years and 10 months, he underwent bilateral nephrectomy and received a kidney transplant from a deceased 18-year-old donor. Despite moderate long-term immunosuppression of prednisone (20 mg/48 h) and azathioprine (62.5 mg/day), at the last visit in September 2022, he was well, normotrophic, with a serum creatinine of 157 µmol/l (eGFR 41 ml/min/1.73 m) and no haematuria, proteinuria or hypertension. Except for benign skin lesions due to azathioprine, and undergoing an aortic valve replacement and an aortic aneurysm repair in adulthood, the now 58-year-old man has had no major complications.
CONCLUSIONS
We speculate that stable and unmodified immunosuppressive therapy, started before the era of calcineurin inhibitors, the lack of significant rejection episodes, the absence of donor-specific antibodies, and the young donor age have contributed to maintaining exceptional long-term kidney transplant survival. Luck, a robust health system and an adherent patient are also important. To the best of our knowledge, this is the longest functioning kidney transplant from a deceased donor performed in a child worldwide. Despite its risky nature at the time, this transplant paved the way for others.
Topics: Male; Child; Humans; Middle Aged; Adolescent; Immunosuppressive Agents; Azathioprine; Graft Survival; Tissue Donors; Kidney; Graft Rejection
PubMed: 36929387
DOI: 10.1007/s00467-023-05901-5 -
Alimentary Pharmacology & Therapeutics Apr 2006Azathioprine is widely used in the treatment of children with inflammatory bowel disease. The occurrence and type of adverse events to azathioprine may be related to...
BACKGROUND
Azathioprine is widely used in the treatment of children with inflammatory bowel disease. The occurrence and type of adverse events to azathioprine may be related to thiopurine S-methyltransferase (TPMT) enzyme activity and to inosine triphophate pyrophosphatase (ITPase) deficiency.
AIM
Investigate frequencies of functional TPMT polymorphisms and ITPA polymorphisms and their association with the occurrence of adverse events during azathioprine therapy in a paediatric inflammatory bowel disease population.
METHODS
Seventy-two azathioprine treated paediatric inflammatory bowel disease patients, 47% girls, mean age 12.5 years (range 6.5-17.5), were assessed for TPMT and ITPA polymorphisms and for adverse events. The relation between polymorphisms and adverse events is evaluated.
RESULTS
Of all azathioprine treated patients, 11 experienced an adverse event for which azathioprine was stopped: pancreatitis (n = 4), leucopenia (n = 2) and 'general malaise' (n = 5). Of the 11 patients who stopped azathioprine because of adverse events, 10 had wild-type alleles for all investigated genotypes. Genotyping of ITPA 94C>A polymorphisms showed that two patients were homozygous, both tolerated azathioprine well.
CONCLUSIONS
No association of functional ITPA and TPMT polymorphisms and the occurrence of azathioprine related adverse events could be detected. Pharmacogenetic assessment prior to thiopurine therapy does not seem warranted.
Topics: Adolescent; Azathioprine; Chi-Square Distribution; Child; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukopenia; Male; Methyltransferases; Pancreatitis; Polymorphism, Genetic; Pyrophosphatases; Inosine Triphosphatase
PubMed: 16611274
DOI: 10.1111/j.1365-2036.2006.02853.x -
Journal of Medicine and Life Jun 2022The cause of all small bowel obstruction in 60-75% of cases is adhesive development. The first and main method for adhesion prevention is undoubtedly the surgical...
The cause of all small bowel obstruction in 60-75% of cases is adhesive development. The first and main method for adhesion prevention is undoubtedly the surgical technique, but the prevention of adhesive development is still actual. We aimed to study macroscopic and microscopic peculiarities of the intestine, peritoneum, and scars of the anterolateral abdominal wall. Also, immunological blood changes were observed in rats with the experimental created adhesive disease on the background of azathioprine introduction. The experiment was conducted on 40 rats divided into 2 subgroups: 20 animals as an experimental group (EG1) and 20 as a control group (CG1). Animals from EG received azathioprine (Moshimerampreparaty named by N.A. Semashko, Russia) in a dosage of 1 mg/100g of weight once a day for the first 3 days (starting from the day of surgery). The control group did not receive any drugs. All 40 rats survived the postoperative period. Rats were removed from the experiment on the 7 day after the operation. There were significant statistical differences in most indicators between the experimental and control groups. Phagocytic index (PI) was reduced by 4.55 due to the natural reaction of the rat organism to the surgery. Indicators of EG were a slight decrease in leukocytes and lymphocytes by 0.3 and 0.9, respectively, a moderate decrease in T-lymphocytes by no more than 2.0, and a decrease in phagocytic activity by 5.8. Immunosuppression with azathioprine significantly reduced the frequency and severity of the adhesive process of the abdominal cavity. Used in the recommended dose does not significantly inhibit important indicators of immunity and does not affect wound healing processes.
Topics: Adhesives; Animals; Azathioprine; Immunosuppression Therapy; Peritoneum; Rats; Tissue Adhesions
PubMed: 35928349
DOI: 10.25122/jml-2021-0371