Azatioprina

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. []