アザチオプリン
概要
説明
作用機序
アザチオプリンは、体内での6-メルカプトプリンへの変換によって作用します . 6-メルカプトプリンはさらに代謝されて、プリン生合成を阻害する活性代謝産物となります。 この阻害は、特に免疫系の細胞などの急速に分裂する細胞の増殖を低下させます . アザチオプリンの主な分子標的は、プリン生合成に関与する酵素、例えば、ヒポキサンチン-グアニンホスホリボシルトランスフェラーゼやチオプリンS-メチルトランスフェラーゼなどです . これらの経路は最終的に、免疫応答の抑制につながります .
科学的研究の応用
Autoimmune Diseases
Azathioprine is commonly prescribed for several autoimmune diseases, including:
- Rheumatoid Arthritis : It helps reduce inflammation and slow disease progression.
- Lupus Nephritis : Used as part of a regimen to manage kidney inflammation associated with systemic lupus erythematosus.
- Crohn's Disease and Ulcerative Colitis : Functions as a maintenance therapy to induce and maintain remission in inflammatory bowel disease .
Organ Transplantation
In renal transplantation, azathioprine is utilized as an immunosuppressant to prevent organ rejection. It is often combined with other immunosuppressive agents to enhance efficacy while minimizing toxicity .
Dermatological Conditions
Azathioprine is also indicated for various skin conditions such as:
- Severe Atopic Dermatitis : Helps control severe eczema that does not respond to conventional therapies.
- Lupus Erythematosus : Used in cases where skin manifestations are prominent and require systemic treatment .
Comparative Data Table
| Application | Indication | Dosage Form | Monitoring Requirements |
|---|---|---|---|
| Rheumatoid Arthritis | Chronic inflammation | Oral/Injection | Regular blood tests for liver function |
| Lupus Nephritis | Kidney inflammation | Oral/Injection | Regular blood tests for kidney function |
| Crohn's Disease | Inflammatory bowel disease | Oral | Regular blood tests for hematological status |
| Organ Transplantation | Prevention of rejection | Oral/Injection | Close monitoring for signs of rejection |
| Severe Atopic Dermatitis | Persistent eczema | Oral | Monitoring for skin reactions |
Case Study 1: Azathioprine in Ulcerative Colitis
A comprehensive review highlighted the role of azathioprine in maintaining remission in patients with ulcerative colitis. The study noted that while azathioprine has been effective, there are concerns regarding its side effects and the need for regular monitoring to manage potential adverse reactions .
Case Study 2: Azathioprine in Renal Transplantation
In a clinical trial involving renal transplant patients, azathioprine was shown to significantly reduce the incidence of acute rejection episodes when used alongside corticosteroids. The study underscored the importance of individualized dosing and monitoring strategies to optimize outcomes while minimizing risks .
準備方法
アザチオプリンは、複数段階のプロセスを経て合成されます。 主な合成経路は、6-メルカプトプリンと1-メチル-4-ニトロ-5-イミダゾールの反応を含みます . 反応条件は、通常、ジメチルホルムアミドなどの溶媒と水酸化ナトリウムなどの塩基の使用を含みます。 反応は、中間体の形成を経て進行し、その後環化してアザチオプリンが生成されます .
アザチオプリンの工業生産方法は、同様の合成経路を採用していますが、大規模生産向けに最適化されています。 これには、連続フロー反応器や自動システムの使用が含まれ、品質と収率の一貫性を確保しています .
化学反応の分析
アザチオプリンは、以下のを含むいくつかのタイプの化学反応を起こします。
酸化: アザチオプリンは、さまざまな代謝産物を形成するように酸化される可能性があります。
これらの反応で使用される一般的な試薬と条件には、酸化剤として過酸化水素、還元剤として水素化ホウ素ナトリウムなどがあります . これらの反応から生成される主な生成物には、6-チオ尿酸と、さまざまなアザチオプリンの置換誘導体などがあります .
科学研究の応用
アザチオプリンは、幅広い科学研究の応用があります。
類似化合物との比較
アザチオプリンは、6-メルカプトプリンやチオグアニンなど、チオプリン系薬剤の一種です . これらの化合物と比較して、アザチオプリンは、硫黄原子に結合した追加のイミダゾール環を含む独特の構造を持っています . この構造の違いにより、アザチオプリンは独特の薬物動態プロファイルを示し、特定の臨床用途に適しています .
類似化合物
6-メルカプトプリン: 主に白血病や自己免疫疾患の治療に使用されます.
チオグアニン: 急性骨髄性白血病の治療に使用されます.
メトトレキセート: 癌や自己免疫疾患の治療に使用される別の免疫抑制剤です.
アザチオプリンは、その独特の構造と作用機序により、さまざまな自己免疫疾患の治療や臓器移植拒絶反応の予防に有効な薬剤となっています .
生物活性
Azathioprine (AZA) is a purine analog widely used as an immunosuppressant in various medical conditions, particularly in the management of autoimmune diseases and organ transplantation. This article delves into its biological activity, including its mechanism of action, metabolism, clinical applications, and associated risks.
Azathioprine is a prodrug that is metabolized into its active forms, primarily 6-mercaptopurine (6-MP) and 6-thioguanine nucleotides (6-TGN). The conversion occurs through enzymatic pathways involving hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thiopurine methyltransferase (TPMT) . The active metabolites inhibit purine synthesis, which is critical for DNA replication and cell division. This mechanism is particularly effective against lymphocytes, which rely on the de novo pathway for purine synthesis due to their limited salvage pathway capabilities .
Metabolism
The metabolism of azathioprine involves several key enzymes:
- TPMT : Variability in TPMT activity among individuals can significantly affect the therapeutic response and toxicity of AZA. Low TPMT activity leads to increased levels of 6-TGN, enhancing efficacy but also raising the risk of myelosuppression .
- Xanthine oxidase : This enzyme competes with TPMT in the metabolism of 6-MP, influencing the levels of active metabolites and their effects .
Table 1 summarizes the metabolic pathways and their implications for therapy:
| Enzyme | Role in Metabolism | Clinical Implications |
|---|---|---|
| HPRT | Converts AZA to 6-MP | Essential for activation of AZA |
| TPMT | Converts 6-MP to 6-TGN | Low activity increases risk of toxicity |
| Xanthine oxidase | Competes with TPMT | Influences therapeutic levels of 6-TGN |
Clinical Applications
Azathioprine is primarily used in:
- Rheumatoid Arthritis : It helps manage symptoms and prevent disease progression.
- Organ Transplantation : AZA is employed to prevent rejection by suppressing the immune response.
- Inflammatory Bowel Disease (IBD) : It maintains remission in conditions like Crohn's disease and ulcerative colitis .
Case Studies
- Kidney Transplant Patient with Diarrhea : A case study reported a renal transplant patient who developed severe diarrhea while on AZA. Despite normal renal function, high levels of 6-TGN were noted, leading to a change in therapy that resolved gastrointestinal symptoms .
- Undetectable 6-TGN Levels : Another patient experienced acute cellular rejection despite receiving adequate doses of AZA. Subsequent testing revealed undetectable levels of 6-TGN, indicating potential issues with drug metabolism or adherence .
Efficacy and Safety Profile
The efficacy of azathioprine can vary based on genetic factors affecting metabolism. Studies indicate that patients with low TPMT activity benefit from lower doses to avoid toxicity, while those with high activity may require higher doses for therapeutic effect .
Risks Associated with Azathioprine
While AZA is effective, it carries risks:
- Myelosuppression : A significant risk associated with high levels of 6-TGN.
- Cancer Risk : There is an established association between AZA use and an increased risk of lymphoma among patients with IBD . However, some studies suggest a protective effect against colorectal cancer .
Table 2 outlines the potential adverse effects linked to azathioprine:
| Adverse Effect | Description | Risk Factors |
|---|---|---|
| Myelosuppression | Decreased blood cell production | Low TPMT activity |
| Lymphoma | Increased risk in IBD patients | Long-term use |
| Hepatotoxicity | Liver damage due to metabolite accumulation | High doses or genetic predisposition |
特性
IUPAC Name |
6-(3-methyl-5-nitroimidazol-4-yl)sulfanyl-7H-purine |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C9H7N7O2S/c1-15-4-14-7(16(17)18)9(15)19-8-5-6(11-2-10-5)12-3-13-8/h2-4H,1H3,(H,10,11,12,13) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
LMEKQMALGUDUQG-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CN1C=NC(=C1SC2=NC=NC3=C2NC=N3)[N+](=O)[O-] |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C9H7N7O2S |
Source
|
| Record name | AZATHIOPRINE | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/19837 | |
| Description | CAMEO Chemicals is a chemical database designed for people who are involved in hazardous material incident response and planning. CAMEO Chemicals contains a library with thousands of datasheets containing response-related information and recommendations for hazardous materials that are commonly transported, used, or stored in the United States. CAMEO Chemicals was developed by the National Oceanic and Atmospheric Administration's Office of Response and Restoration in partnership with the Environmental Protection Agency's Office of Emergency Management. | |
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| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Related CAS |
55774-33-9 (hydrochloride salt) |
Source
|
| Record name | Azathioprine [USAN:USP:INN:BAN:JAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000446866 | |
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DSSTOX Substance ID |
DTXSID4020119 |
Source
|
| Record name | Azathioprine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID4020119 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
277.27 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Azathioprine appears as pale yellow crystals or yellowish powder. Decomposes at 243-244 °C. Used for the treatment of rheumatoid arthritis. A known carcinogen., Solid |
Source
|
| Record name | AZATHIOPRINE | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/19837 | |
| Description | CAMEO Chemicals is a chemical database designed for people who are involved in hazardous material incident response and planning. CAMEO Chemicals contains a library with thousands of datasheets containing response-related information and recommendations for hazardous materials that are commonly transported, used, or stored in the United States. CAMEO Chemicals was developed by the National Oceanic and Atmospheric Administration's Office of Response and Restoration in partnership with the Environmental Protection Agency's Office of Emergency Management. | |
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| Record name | Azathioprine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015128 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
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Solubility |
>41.6 [ug/mL] (The mean of the results at pH 7.4), less than 1 mg/mL at 73 °F (NTP, 1992), Insoluble, Very slightly soluble in ethanol and chloroform; sparingly soluble in dilute mineral acids; soluble in dilute alkali solutions, Insoluble in water, 1.07e+00 g/L |
Source
|
| Record name | SID26670994 | |
| Source | Burnham Center for Chemical Genomics | |
| URL | https://pubchem.ncbi.nlm.nih.gov/bioassay/1996#section=Data-Table | |
| Description | Aqueous solubility in buffer at pH 7.4 | |
| Record name | AZATHIOPRINE | |
| Source | CAMEO Chemicals | |
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| Description | CAMEO Chemicals is a chemical database designed for people who are involved in hazardous material incident response and planning. CAMEO Chemicals contains a library with thousands of datasheets containing response-related information and recommendations for hazardous materials that are commonly transported, used, or stored in the United States. CAMEO Chemicals was developed by the National Oceanic and Atmospheric Administration's Office of Response and Restoration in partnership with the Environmental Protection Agency's Office of Emergency Management. | |
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| Record name | Azathioprine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00993 | |
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| Record name | AZATHIOPRINE | |
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| Record name | Azathioprine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015128 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Mechanism of Action |
Azathioprine's mechanism of action is not entirely understood but it may be related to inhibition of purine synthesis, along with inhibition of B and T cells. 6-thioguanine triphosphate, a metabolite of azathioprine, modulates activation of rac1 when costimulated with CD28, inducing T cell apoptosis. This may be mediated through rac1's action on mitogen-activated protein kinase, NF-kappaB., Following exposure to nucleophiles ... azathioprine is cleaved to 6-mercaptopurine which, in turn, is converted to additional metabolites that inhibit de novo purine synthesis. 6-Thio-IMP, a fraudulent nucleotide, is converted to 6-thio-GMP and finally to 6-thio-GTP, which is incorporated into DNA and gene translation is inhibited. Cell proliferation is prevented, inhibiting a variety of lymphocyte functions., Azathioprine (AZA), one of the antimetabolite drugs, is a purine analog that is more potent than the prototype 6-mercaptopurine, as an inhibitor of cell replication. Immunosuppression likely occurs because of the ability of the drug to inhibit purine biosynthesis. ... Although T-cell functions are the primary targets for this drug, inhibition of /(natural killer cells)/ NK function and macrophage activities has also been reported., Azathioprine inhibits DNA synthesis and, as a purine antimetabolite, exerts its effect on activated lymphocytes, which requires purines during their proliferative phase. It inhibits both cellular and humoral responses, but does not interfere with phagocytosis or interferon production. It is a nonspecific cytotoxic agent. Its immunosuppressive effect is believed to be due to mercaptopurine, to which it is metabolized., The exact mechanism of immunosuppressive action is unknown since the exact mechanism of the immune response itself is complex and not completely understood. The immunosuppressive effects of azathioprine involve a greater suppression of delayed hypersensitivity and cellular cytotoxicity tests than of antibody responses. Azathioprine antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins; it may also interfere with cellular metabolism and inhibit mitosis., For more Mechanism of Action (Complete) data for AZATHIOPRINE (6 total), please visit the HSDB record page. |
Source
|
| Record name | Azathioprine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00993 | |
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| Record name | AZATHIOPRINE | |
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| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7084 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Color/Form |
Pale yellow crystals from 50% aq acetone | |
CAS No. |
446-86-6 |
Source
|
| Record name | AZATHIOPRINE | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/19837 | |
| Description | CAMEO Chemicals is a chemical database designed for people who are involved in hazardous material incident response and planning. CAMEO Chemicals contains a library with thousands of datasheets containing response-related information and recommendations for hazardous materials that are commonly transported, used, or stored in the United States. CAMEO Chemicals was developed by the National Oceanic and Atmospheric Administration's Office of Response and Restoration in partnership with the Environmental Protection Agency's Office of Emergency Management. | |
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| Record name | Azathioprine | |
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| Record name | Azathioprine [USAN:USP:INN:BAN:JAN] | |
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| URL | https://www.drugbank.ca/drugs/DB00993 | |
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| Record name | azathioprine | |
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| Record name | Azathioprine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015128 | |
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Melting Point |
469 to 471 °F (decomposes) (NTP, 1992), dec 243-244 °C, 243.5 °C |
Source
|
| Record name | AZATHIOPRINE | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/19837 | |
| Description | CAMEO Chemicals is a chemical database designed for people who are involved in hazardous material incident response and planning. CAMEO Chemicals contains a library with thousands of datasheets containing response-related information and recommendations for hazardous materials that are commonly transported, used, or stored in the United States. CAMEO Chemicals was developed by the National Oceanic and Atmospheric Administration's Office of Response and Restoration in partnership with the Environmental Protection Agency's Office of Emergency Management. | |
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| Record name | Azathioprine | |
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| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7084 | |
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| Record name | Azathioprine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015128 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Synthesis routes and methods
Procedure details
Retrosynthesis Analysis
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Feasible Synthetic Routes
Q1: How does Azathioprine exert its immunosuppressive effect?
A1: Azathioprine acts as a prodrug, metabolizing into 6-mercaptopurine (6-MP). [] 6-MP undergoes further transformations, ultimately forming active thioguanine nucleotides (6-TGNs). [] These 6-TGNs are responsible for the immunosuppressive effect by incorporating into DNA and inhibiting purine synthesis, disrupting DNA and RNA synthesis, thereby primarily affecting rapidly proliferating cells like lymphocytes. []
Q2: Can you elaborate on the role of 6-Thio-GTP, a metabolite of Azathioprine, in immunosuppression?
A2: 6-Thio-GTP, generated from Azathioprine, plays a crucial role in immunosuppression by inhibiting the activation of Rac1 and Rac2 GTPases in T cells. [] This inhibition disrupts the Vav1-Rac signaling pathway, essential for T cell activation and function. []
Q3: What is the significance of Ezrin-Radixin-Moesin proteins in Azathioprine's mechanism?
A3: Azathioprine, through its metabolite 6-Thio-GTP, blocks the dephosphorylation of Ezrin-Radixin-Moesin (ERM) proteins in T cells by inhibiting Vav1 exchange activity on Rac proteins. [] This blockade of ERM dephosphorylation ultimately disrupts the formation of a stable interaction between T cells and antigen-presenting cells (APCs), known as the immunological synapse, hindering T cell activation and proliferation. []
Q4: What is the molecular formula and weight of Azathioprine?
A4: The molecular formula of Azathioprine is C9H7N7O2S, and its molecular weight is 277.27 g/mol.
Q5: Is there information available on Azathioprine's material compatibility or stability under various conditions within the provided research?
A5: The provided research papers primarily focus on the clinical aspects and applications of Azathioprine. They do not delve into material compatibility and stability studies.
Q6: Does Azathioprine exhibit catalytic properties?
A6: Azathioprine is not known to possess catalytic properties. It functions as an immunosuppressive agent by interfering with DNA synthesis and cellular processes rather than catalyzing chemical reactions.
Q7: Has computational chemistry been employed to study Azathioprine?
A7: While the provided research papers primarily focus on clinical studies, one paper mentions computational approaches. [] The study suggests using computational methods for dosage determination to avoid toxicity or undertreatment of drugs like mercaptopurine and Azathioprine. []
Q8: What are the challenges associated with Azathioprine formulation, and how can they be addressed?
A9: While not explicitly discussed in the papers, one study focuses on developing Azathioprine tablets for colon-targeted delivery. [] This suggests challenges related to its absorption and potential degradation in the upper gastrointestinal tract. The study explores using Eudragit-S, Eudragit-L, and cellulose acetate phthalate coatings to achieve colon-targeted release, highlighting the role of formulation strategies in enhancing Azathioprine delivery. []
Q9: Is there information available regarding SHE regulations specific to Azathioprine in the provided research?
A9: The provided research predominantly centers on clinical findings and doesn't encompass specific SHE regulatory information concerning Azathioprine.
Q10: How is Azathioprine metabolized in the body?
A11: Azathioprine is metabolized in a complex pathway. Initially, it's converted to 6-mercaptopurine, which then undergoes various transformations. One crucial enzyme involved is Thiopurine methyltransferase (TPMT). [, , , ]
Q11: Why is TPMT crucial in Azathioprine therapy?
A12: TPMT plays a vital role in inactivating 6-mercaptopurine, a metabolite of Azathioprine. [, , , , ] Individuals with low TPMT activity may experience a buildup of thioguanine nucleotides, leading to severe myelosuppression. [, , ] Therefore, assessing TPMT activity before and during therapy is crucial for guiding dosage and preventing toxicity. [, , , ]
Q12: How does Azathioprine's metabolism influence its dosing?
A13: Azathioprine's complex metabolism, particularly its dependence on TPMT activity, necessitates personalized dosing. [, , ] Patients with low TPMT activity require significantly reduced doses to avoid life-threatening myelosuppression. [, , ] Monitoring leukocyte and platelet counts alongside thioguanine nucleotide concentrations is crucial for dose adjustment. []
Q13: Are there factors beyond TPMT that affect Azathioprine's effectiveness?
A14: Yes, while TPMT is critical, other factors influencing Azathioprine's disposition include drug interactions and patient characteristics. For example, Allopurinol inhibits xanthine oxidase, another enzyme involved in mercaptopurine metabolism, impacting Azathioprine's effects. [] Additionally, age, sex, and renal function can affect TPMT activity and, consequently, Azathioprine's action. []
Q14: Can you provide specific examples of Azathioprine's efficacy from the provided research?
A14: The research highlights Azathioprine's efficacy in several clinical scenarios:
- Ulcerative Colitis: A study demonstrated that Azathioprine maintenance therapy effectively prevents relapse in patients with ulcerative colitis who achieved remission while on the drug. [] This finding has significant implications for managing this chronic condition.
- Crohn's Disease: Azathioprine proved beneficial in preventing postoperative recurrence of Crohn's disease. [] A systematic review highlighted a reduced risk of both clinical and severe endoscopic recurrence with Azathioprine or 6-mercaptopurine use after surgery. []
Q15: Is there information on Azathioprine resistance mechanisms in the research papers?
A15: The research papers provided do not delve into specific Azathioprine resistance mechanisms.
Q16: What are the known side effects of Azathioprine?
A16: While the focus is on scientific aspects, the papers do mention some side effects observed in clinical settings:
- Myelosuppression: This is a significant concern, particularly in individuals with low TPMT activity. [, , ] It manifests as a reduction in blood cell counts, potentially leading to leukopenia, anemia, and thrombocytopenia.
- Gastrointestinal Issues: Gastrointestinal symptoms are reported, and while not detailed, they are often a reason for discontinuing treatment. []
- Hepatotoxicity: Azathioprine can potentially cause liver damage, evident through elevated liver enzyme levels. [, ]
- Pancreatitis: Azathioprine-induced pancreatitis is a rare but serious adverse effect. [, ]
Q17: Are there strategies to enhance Azathioprine's delivery to specific targets?
A18: One of the research papers investigates delivering Azathioprine specifically to the colon. [] The researchers achieved this by coating Azathioprine tablets with Eudragit-S, Eudragit-L, and cellulose acetate phthalate polymers. [] This approach aims to bypass absorption in the upper gastrointestinal tract, potentially reducing side effects and improving drug delivery to the colon, which is relevant for treating inflammatory bowel diseases.
Q18: What biomarkers are crucial for Azathioprine therapy?
A18: Monitoring specific biomarkers is crucial during Azathioprine treatment:
- Thiopurine methyltransferase (TPMT) activity: Measuring TPMT activity before and during treatment helps personalize dosage and minimize the risk of severe myelosuppression. [, , , ]
- Blood Cell Counts: Regular monitoring of leukocyte and platelet counts helps detect myelosuppression early on. []
- Thioguanine Nucleotide (6-TGN) Levels: Measuring 6-TGN levels can help optimize the dosage and balance efficacy with the risk of toxicity. []
Q19: What analytical methods are used to characterize and quantify Azathioprine?
A19: The research papers primarily focus on the clinical aspects and do not provide detailed descriptions of specific analytical methods used for Azathioprine characterization and quantification.
Q20: Is there information on Azathioprine's environmental impact or degradation in the provided research?
A20: The environmental impact and degradation of Azathioprine are not discussed in the provided research papers.
Q21: Do the papers provide details on analytical method validation or quality control measures for Azathioprine?
A21: The provided research primarily focuses on clinical findings and does not include specifics regarding analytical method validation, quality control, or assurance for Azathioprine.
Q22: Does Azathioprine induce an immune response itself?
A22: The provided research papers do not delve into Azathioprine's potential to induce an immune response (immunogenicity).
Q23: What is known about Azathioprine's interaction with drug transporters or drug-metabolizing enzymes?
A25: One crucial interaction highlighted is the impact of Allopurinol on Azathioprine's metabolism. [] Allopurinol, often used to treat gout, inhibits xanthine oxidase, an enzyme involved in mercaptopurine (Azathioprine's metabolite) breakdown. [] This interaction can increase the risk of Azathioprine toxicity, particularly myelosuppression, by increasing 6-mercaptopurine levels.
Q24: Is there information on Azathioprine's biocompatibility and biodegradability within the provided research?
A24: The provided research papers do not explicitly address Azathioprine's biocompatibility and biodegradability.
Q25: Are there alternatives to Azathioprine for the conditions discussed, and how do they compare?
A25: The provided research does mention some alternatives to Azathioprine:
- Mycophenolate Mofetil (MMF): MMF is another immunosuppressive agent. One study compared Azathioprine and MMF for kidney transplant recipients and found that while MMF reduced acute rejection, it did not show a significant advantage over Azathioprine in preventing graft loss. []
- Cyclosporine: This immunosuppressant is often used in transplantation. Research indicates that while cyclosporine is effective, it might carry a higher risk of certain side effects like impaired fibrinolytic activity compared to Azathioprine. []
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