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Acta Neurologica Belgica Oct 2023Current myasthenia gravis guidelines recommend the use of azathioprine as first-line steroid sparing agent. However, due to its high cost, compliance to azathioprine is... (Review)
Review
Current myasthenia gravis guidelines recommend the use of azathioprine as first-line steroid sparing agent. However, due to its high cost, compliance to azathioprine is low in developing countries. To determine the efficacy and safety of the cheaper methotrexate as an alternative immunosuppressant, Medline/Pubmed, Embase and Cochrane databases and references were searched for clinical trials and observational studies using the search terms: "Myasthenia OR Myasthenia Gravis OR anti AchR antibody positive Myasthenia Gravis OR anti-MuSK antibody Myasthenia Gravis OR MG" AND "Methotrexate". Of 78 possible articles, only 4 were selected using the following eligibility criteria: population: generalized MG patients; intervention: methotrexate; and outcome: effectiveness, steroid sparing efficacy and adverse effects. Two clinical trials and one observational study noted improvement in different MG outcomes in patients given methotrexate. While one randomized controlled clinical trial concluded that methotrexate has no steroid sparing benefit, a single blinded clinical trial established that methotrexate was a better steroid sparing agent than azathioprine starting at 10th month of use. Adverse effects were rare with non-specific pain and elevated transaminases as the most common complaints. Based on available evidence, MTX may be a safe and effective alternative to AZA as steroid sparing agent in developing countries.
Topics: Humans; Methotrexate; Azathioprine; Immunosuppressive Agents; Myasthenia Gravis; Prednisone; Drug-Related Side Effects and Adverse Reactions; Randomized Controlled Trials as Topic; Observational Studies as Topic
PubMed: 36967437
DOI: 10.1007/s13760-023-02242-w -
International Journal of Pharmaceutical... 2023Azathioprine is used to treat the symptoms of rheumatoid arthritis and for the prevention of transplant rejection. A review of the therapeutic uses of Azathioprine... (Review)
Review
Azathioprine is used to treat the symptoms of rheumatoid arthritis and for the prevention of transplant rejection. A review of the therapeutic uses of Azathioprine reveals the need for flexibility in dosing. This flexibility is readily achieved using an oral liquid dosage form. However, no commercial liquid dosage form of Azathioprine currently exists. Azathioprine is commercially available only as a 50-mg tablet. An extemporaneously compounded suspension from pure drug powder would provide a flexible, customizable option to meet unique patient needs with convenient and accurate dosing options. The purpose of this study was to determine the physicochemical and microbiological stability of extemporaneously compounded Azathioprine suspensions in the PCCA Base, SuspendIt. This base is a sugar-free, paraben free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. The study design included two Azathioprine concentrations to provide stability documentation over a bracketed concentration range for eventual use by compounding pharmacists. A robust stability-indicating high-performance liquid chromatographic assay for the determination of the chemical stability of Azathioprine in PCCA SuspendIt was developed and validated. Suspensions of Azathioprine were prepared in PCCA SuspendIt at 10-mg/mL and 50-mg/mL concentrations, selected to represent a range within which the drug is commonly dosed. Samples were stored in amber plastic prescription bottles at two temperature conditions (5°C and 25°C). Samples were assayed initially, and on the following time points (days): 7, 14, 28, 49, 63, 90, 119, and 182. Physical data such as pH, viscosity, and appearance were also noted. Microbiological stability was tested. All measurements were obtained in triplicate. A stable extemporaneous product is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period and is protected against microbial growth. The study showed that Azathioprine concentrations did not go below 96.8% of the label claim (initial drug concentration) at both temperatures studied. No microbial growth was observed. The pH values remained constant. The viscosity of the suspensions allowed easy re-dispersal of the drug particles upon shaking. This study demonstrates that Azathioprine is physically, chemically, and microbiologically stable in PCCA SuspendIt for 182 days in the refrigerator and at room temperature, thus providing a viable, compounded alternative for Azathioprine in a liquid dosage form, with an extended beyond-use date to meet patient needs.
Topics: Humans; Azathioprine; Drug Stability; Drug Compounding; Chromones; Suspensions; Chromatography, High Pressure Liquid; Drug Storage; Administration, Oral
PubMed: 37595175
DOI: No ID Found -
Inflammatory Bowel Diseases Jun 20166-thioguanine nucleotides levels are associated with clinical remission in patients with inflammatory bowel disease (IBD) on thiopurine monotherapy. Recently, few... (Review)
Review
6-thioguanine nucleotides levels are associated with clinical remission in patients with inflammatory bowel disease (IBD) on thiopurine monotherapy. Recently, few studies investigated the interaction between thiopurine metabolism and anti-tumor necrosis factor therapy among patients with IBD on combotherapy. Two studies demonstrated that infliximab therapy increases 6-thioguanine nucleotides level, while such effect could not be observed with adalimumab. Three studies showed that a Delta mean corpuscular volume >7 and high 6-thioguanine nucleotides levels are associated with favorable outcomes, i.e., greater mucosal healing rates, and have a positive impact on the pharmacokinetics of infliximab. These results suggest a synergistic effect between thiopurine metabolism and anti-tumor necrosis factor therapy, especially with infliximab. We propose here some algorithms for clinical practice integrating thiopurine metabolism in patients with IBD on combotherapy. Further randomized controlled trials are needed to further investigate the relationships between thiopurine metabolism and anti-tumor necrosis factor therapy and to establish the clinical utility of measuring thiopurines' metabolites in these patients in clinical practice. Whether measuring thiopurine metabolism can be used to guide decision-making in patients with IBD on combotherapy when considering drug de-escalation or discontinuation will require further investigation.
Topics: Algorithms; Azathioprine; Drug Interactions; Drug Therapy, Combination; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Tumor Necrosis Factor-alpha
PubMed: 26978723
DOI: 10.1097/MIB.0000000000000737 -
Annals of Internal Medicine Aug 2022Thiopurines are an important class of immunosuppressants despite their risk for hematopoietic toxicity and narrow therapeutic indices. Benign neutropenia related to an...
BACKGROUND
Thiopurines are an important class of immunosuppressants despite their risk for hematopoietic toxicity and narrow therapeutic indices. Benign neutropenia related to an variant (rs2814778-CC) is common among persons of African ancestries.
OBJECTIVE
To test whether rs2814778-CC was associated with azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine dosing.
DESIGN
Retrospective cohort study.
SETTING
Two tertiary care centers.
PATIENTS
Thiopurine users with White or Black race.
MEASUREMENTS
Azathioprine discontinuation attributed to hematopoietic toxicity. Secondary outcomes included weight-adjusted final dose, leukocyte count, and change in leukocyte count.
RESULTS
The rate of azathioprine discontinuation attributed to hematopoietic toxicity was 3.92 per 100 person-years among patients with the CC genotype ( = 101) and 1.34 per 100 person-years among those with the TT or TC genotype ( = 1365) (hazard ratio [HR] from competing-risk model, 2.92 [95% CI, 1.57 to 5.41]). The risk remained significant after adjustment for race (HR, 2.61 [CI, 1.01 to 6.71]). The risk associated with race alone (HR, 2.13 [CI, 1.21 to 3.75]) was abrogated by adjustment for genotype (HR, 1.13 [CI, 0.48 to 2.69]). Lower last leukocyte count and lower dosing were significant among patients with the CC genotype. Lower dosing was validated in an external cohort of 94 children of African ancestries prescribed the thiopurine 6-mercaptopurine (6-MP) for acute lymphoblastic leukemia. The CC genotype was independently associated with lower 6-MP dose intensity relative to the target daily dose of 75 mg/m (median, 0.83 [IQR, 0.70 to 0.94] for the CC genotype vs. 0.94 [IQR, 0.72 to 1.13] for the TT or TC genotype; = 0.013).
LIMITATIONS
Unmeasured confounding; data limited to tertiary centers.
CONCLUSION
Patients with the CC genotype had higher risk for azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine doses. Genotype was associated with those risks, even after adjustment for race.
PRIMARY FUNDING SOURCE
National Institutes of Health.
Topics: Azathioprine; Child; Cohort Studies; Genotype; Humans; Mercaptopurine; Retrospective Studies
PubMed: 35724382
DOI: 10.7326/M21-4675 -
Polish Archives of Internal Medicine Sep 2022Autoimmune hepatitis (AIH) is an acute or chronic inflammatory disease of the liver caused by an immune response of unknown origin. It affects people from all ethnic... (Review)
Review
Autoimmune hepatitis (AIH) is an acute or chronic inflammatory disease of the liver caused by an immune response of unknown origin. It affects people from all ethnic groups irrespective of age or sex. AIH is characterized by hyperglobulinemia, presence of circulating autoantibodies, and liver inflammation. The clinical picture of the disease varies from asymptomatic or mild to severe acute hepatitis or liver failure. A timely and prompt diagnosis is of utmost importance to prevent progression to advanced liver disease by immediate initiation of immunosuppressive treatment. So far, several diagnostic scoring systems have been proposed, which incorporated demographic data as well as biochemical, clinical, and histological characteristics of the disease. However, due to the high heterogeneity of the disease presentation, diagnosis of AIH remains challenging. Most patients initially respond to first‑ line treatment, which consists of corticosteroids combined with azathioprine or mycophenolate mofetil. However, insufficient response to the treatment and intolerance due to side effects are common, so a significant proportion of patients require second- and / or third‑ line therapies. Herein, we review the challenges and recent advances in AIH diagnosis and management.
Topics: Autoantibodies; Azathioprine; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid
PubMed: 36093593
DOI: 10.20452/pamw.16334 -
Brain and Nerve = Shinkei Kenkyu No... May 2023Treatments for acute attacks of neuromyelitis optica (NMO) include steroid pulse therapy, plasma exchange, and intravenous immunoglobulin. Oral immunosuppressants, such...
Treatments for acute attacks of neuromyelitis optica (NMO) include steroid pulse therapy, plasma exchange, and intravenous immunoglobulin. Oral immunosuppressants, such as prednisolone and azathioprine, have also been used to prevent relapse. Recently, biologic agents such as eculizumab, satralizumab, inebilizumab, and rituximab have been approved for use in Japan. Although side effects caused by steroid therapy have been issues for patients in the past, active use of the newly approved biologics is expected to help patients avoid the adverse effects of steroids and improve their qualities of life.
Topics: Humans; Neuromyelitis Optica; Immunosuppressive Agents; Azathioprine; Rituximab; Plasmapheresis; Aquaporin 4
PubMed: 37194518
DOI: 10.11477/mf.1416202364 -
Current Drug Metabolism 2016Thiopurine antimetabolites are important agents for the treatment of severe diseases, such as acute lymphoblastic leukemia and inflammatory bowel disease. Their... (Review)
Review
BACKGROUND
Thiopurine antimetabolites are important agents for the treatment of severe diseases, such as acute lymphoblastic leukemia and inflammatory bowel disease. Their pharmacological actions depend on biotransformation into active thioguanine-nucleotides; intracellular metabolism is mediated by enzymes of the salvage pathway of nucleotide synthesis and relies on polymorphic enzymes involved in thiopurines' catabolism such as thiopurine-S-methyl transferase. Given the enzymes involved in thiopurines' metabolism, it is reasonable to hypothesize that these drugs are able to induce significant oxidative stress conditions, possibly altering their pharmacological activity.
METHODS
A systemic search of peer-reviewed scientific literature in bibliographic databases has been carried out. Both clinical and preclinical studies as well as mechanistic studies have been included to shed light on the role of oxidative stress in thiopurines' pharmacological effects.
RESULTS
Sixty-nine papers were included in our review, allowing us to review the contribution of oxidative stress in the pharmacological action of thiopurines. Thiopurines are catabolized in the liver by xanthine oxidase, with potential production of reactive oxidative species and azathioprine is converted into mercaptopurine by a reaction with reduced glutathione, that, in some tissues, may be facilitated by glutathione- S-transferase (GST). A clear role of GSTM1 in modulating azathioprine cytotoxicity, with a close dependency on superoxide anion production, has been recently demonstrated. Interestingly, recent genome-wide association studies have shown that, for both azathioprine in inflammatory bowel disease and mercaptopurine in acute lymphoblastic leukemia, treatment effects on patients' white blood cells are related to variants of a gene, NUDT15, involved in biotransformation of oxidated nucleotides.
CONCLUSIONS
Basing on previous evidences published in literature, oxidative stress may contribute to thiopurine effects in significant ways that, however, are still not completely elucidated.
Topics: Animals; Antimetabolites; Azathioprine; Biotransformation; Glutathione; Glutathione Transferase; Humans; Liver; Mercaptopurine; Metabolic Detoxication, Phase II; Oxidative Stress; Pharmacogenetics; Polymorphism, Single Nucleotide; Pyrophosphatases; Reactive Oxygen Species; Risk Factors; Xanthine Oxidase
PubMed: 26935390
DOI: 10.2174/1389200217666160303104153 -
Current Gastroenterology Reports Feb 2016Autoimmune hepatitis (AIH) is a complex autoimmune disease characterized by immune-mediated destruction of hepatic parenchyma which can result in cirrhosis, liver... (Review)
Review
Autoimmune hepatitis (AIH) is a complex autoimmune disease characterized by immune-mediated destruction of hepatic parenchyma which can result in cirrhosis, liver failure, and death. Current American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of Liver (EASL) guidelines recommend corticosteroids alone or in combination with azathioprine as first-line treatment strategies. However, a significant proportion of patients may not be able to tolerate or achieve complete biochemical response with these options. In this article, we discuss approaches to these patients and other challenging AIH patient groups such as the asymptomatic, pregnant, elderly, and liver transplant recipients.
Topics: Acute Disease; Azathioprine; Female; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Cirrhosis; Pregnancy; Pregnancy Complications; Treatment Failure
PubMed: 26780632
DOI: 10.1007/s11894-015-0484-7 -
Lupus Science & Medicine Sep 2021Immune dysregulation in SLE and the corresponding immune-modulating and immunosuppressive nature of the treatments may play key roles in infection risk. We compared...
OBJECTIVE
Immune dysregulation in SLE and the corresponding immune-modulating and immunosuppressive nature of the treatments may play key roles in infection risk. We compared serious infection rates among individuals with incident SLE with the general population, and examined the role of treatment initiation in SLE.
METHODS
Newly diagnosed patients with SLE (2006-2013) and general population comparators from the Swedish Lupus Linkage cohort were followed for serious infection through 2016. Adjusted Cox and frailty models estimated the relative risk of first and recurrent infections, respectively. Using a new-user design, rates of serious infections were compared between disease-modifying antirheumatic drugs (DMARDs) and hydroxychloroquine (HCQ) initiators. We then evaluated three DMARDs (azathioprine, mycophenolate mofetil and methotrexate) in multivariable-adjusted models.
RESULTS
Individuals with SLE experienced more infections (22% vs 6%), especially during the first year of follow-up, and recurrent serious infections were also more common (HR=2.22, 95% CI 1.93 to 2.56). DMARDs were associated with a higher rate of serious infection versus HCQ (HR=1.82, 95% CI 1.27 to 2.60), which attenuated after multivariable-adjustment (HR=1.30, 95% CI 0.86 to 1.95). Among DMARDs, azathioprine was associated with infection (HR=2.19, 95% CI 1.14 to 4.21) and mycophenolate mofetil yielded an HR=1.39 (95% CI 0.65 to 2.96) in multivariable-adjusted models compared with methotrexate. Results were comparable across numerous sensitivity analyses.
CONCLUSION
Individuals with incident SLE were 2-4 times more likely to be hospitalised for infection and experienced more recurrent infections than the general population. Among DMARD initiators, azathioprine was associated with the highest rate.
Topics: Antirheumatic Agents; Azathioprine; Hospitalization; Humans; Hydroxychloroquine; Sweden
PubMed: 34526357
DOI: 10.1136/lupus-2021-000510 -
International Journal of Molecular... Jun 2021The electrochemical behavior and the interaction of the immunosuppressive drug azathioprine (AZA) with deoxyribonucleic acid (DNA) were investigated using voltammetric...
The electrochemical behavior and the interaction of the immunosuppressive drug azathioprine (AZA) with deoxyribonucleic acid (DNA) were investigated using voltammetric techniques, mass spectrometry (MS), and scanning electron microscopy (SEM). The redox mechanism of AZA on glassy carbon (GC) was investigated using cyclic and differential pulse (DP) voltammetry. It was proven that the electroactive center of AZA is the nitro group and its reduction mechanism is a diffusion-controlled process, which occurs in consecutive steps with formation of electroactive products and involves the transfer of electrons and protons. A redox mechanism was proposed and the interaction of AZA with DNA was also investigated. Morphological characterization of the DNA film on the electrode surface before and after interaction with AZA was performed using scanning electron microscopy. An electrochemical DNA biosensor was employed to study the interactions between AZA and DNA with different concentrations, incubation times, and applied potential values. It was shown that the reduction of AZA molecules bound to the DNA layer induces structural changes of the DNA double strands and oxidative damage, which were recognized through the occurrence of the 8-oxo-deoxyguanosine oxidation peak. Mass spectrometry investigation of the DNA film before and after interaction with AZA also demonstrated the formation of AZA adducts with purine bases.
Topics: Algorithms; Azathioprine; Biosensing Techniques; Chemical Phenomena; DNA; Macromolecular Substances; Mass Spectrometry; Models, Theoretical; Oxidation-Reduction
PubMed: 34202734
DOI: 10.3390/ijms22136805