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Miscellaneous Drugs during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
Azathioprine is a 6-mercaptopurine derivative and a purine antimetabolite that acts by suppression of T-lymphocytes and cell-mediated immunity. In vivo, the drug is metabolized to mercaptopurine. It is used to treat autoimmune diseases and to prevent transplant rejection. Dose-dependent maternal side effects include bone marrow suppression, increased susceptibility to infection, alopecia, rash, gastrointestinal disturbances, arthralgias, hypersensitivity, pancreatitis, and toxic hepatitis (Berkowitz et al., 1986).
Diseases of Infancy and Childhood
Published in Ayşe Serap Karadağ, Lawrence Charles Parish, Jordan V. Wang, Roxburgh's Common Skin Diseases, 2022
Treatment is dependent on the localization and extent of the disease. If only limited to the skin, watchful waiting may suffice, since the lesions can spontaneously resolve. In cases of severe skin disease, systemic therapies used for the treatment of multiorgan LCH could be employed. Topical corticosteroids, topical tacrolimus, topical nitrogen mustard, psoralen plus ultraviolet A treatment, and systemic corticosteroids may be used in patients with symptomatic or recalcitrant skin lesions. Single bone lesions may also resolve spontaneously. Painful bone lesions may be treated with curettage and/or intralesional steroid injection. Localized radio-therapy could be another treatment option. First-line treatment for patients with multisystemic LCH is prednisone and vinblastine combination. Mercaptopurine is added for patients with risk organ involvement. The second-line treatment choice is cytarabine. Targeted treatments such as vemurafenib, trametinib, and cobimetinib may be used for refractory multisystemic LCH involving risk organs. Prognosis is dependent on the involvement of organs and response to initial systemic therapy.
Inflammatory Bowel Disease
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
Current guidelines suggest that thiopurines have a low risk profile in pregnancy and recommend that women who conceive on these medications should continue them during pregnancy [28, 30, 48]. Women should be counseled not to stop 6-mercaptopurine before conceiving as that may actually increase the risk of fetal loss [62]. Several series suggest that azathioprine/6-mercaptopurine are compatible with breastfeeding [32, 63, 64].
In vitro study of the toxic and teratogenic effects of prednisolone, azathioprine and mycophenolate mofetile on embryological development of rats
Published in Drug and Chemical Toxicology, 2022
Zeliha Fazliogullari, Ahmet Kagan Karabulut, Nadire Unver Dogan, Ismihan Ilknur Uysal, Hasan Acar
Azathioprine (AZ) is a prodrug that inhibits purine metabolism. Quickly metabolized to 6-mercaptopurine (Armenti et al. 2002), it is used in solid organ transplantation, requiring a lowered dose of corticosteroids or other immunosuppressive agents (Woodroffe et al. 2005). The teratogenic effects of AZ crossing the placenta to the embryo have been demonstrated in animal studies and it is thereby placed in the pregnancy medication category D of the FDA's classification scheme (Tuchmann-Duplessis and Mercier-Parot 1968, Schmid 1984, Zachariah et al. 2009). High doses of AZ have shown teratogenic effects in animals, while human fetuses exposed to AZ are subject to low birth weight, prematurity, jaundice, respiratory distress syndrome, and aspiration in the fetuses of mothers, who were kidney recipients (Lessan-Pezeshki 2002).
Use of medications during pregnancy and breastfeeding for Crohn’s disease and ulcerative colitis
Published in Expert Opinion on Drug Safety, 2021
Robyn Laube, Sudarshan Paramsothy, Rupert W Leong
The thiopurine level in breastmilk peaks within four hours of drug ingestion before declining to 10% of this level two hours later [97]. Breastmilk levels are significantly lower than maternal serum levels and lag by one hour [97]. Christensen et al [97] calculated that an infant consuming 150 mL/kg/day breastmilk from a mother taking therapeutic thiopurines would ingest a maximum of 0.0075 mg/kg mercaptopurine, which is <1% of the adult dose. 6-TGN and 6-MMP have not been detected in the serum of breastfed infants [97–100]. A prospective cohort study of women with IBD taking thiopurines while breastfeeding found no adverse effects on infant mental or physical development after a median 3.3 years follow-up [91]. Exposed infants were more likely to experience >2 episodes of the common cold per year (60% vs. 7%) however had no increased rate of overall infections or hospitalizations. No adverse effects of thiopurine exposure in breastfed infants have been reported in other studies [74,99,100]. Further data is required for women with reduced thiopurine-S-methyltransferase (TPMT) activity, in whom the risk of adverse effects may be heightened [98]. Although data is scarce, thioguanine is expected to have a similar safety profile to conventional thiopurines, with lower 6-TGN levels detected in breastmilk (48pmol/L) compared to cord blood (95pmol/8 x 108 RBC) and maternal blood (1740pmol/8 x 108 RBC) [96].
Use of big data in drug development for precision medicine: an update
Published in Expert Review of Precision Medicine and Drug Development, 2019
Tongqi Qian, Shijia Zhu, Yujin Hoshida
Due to the fact that patients might have different genetic backgrounds, the therapeutic window of certain drugs would be also distinct, accordingly raising a more important concern about the personalized drug safety [79]. It could be exemplified by 6-mercaptopurine, which is a drug for acute lymphocytic leukemia and chronic myeloid leukemia. It may take on different side effects in patients with different genetic variants on TPMT, NUDT15, and ITPA [81–83]. Motivated by this fact, genetic tests are necessary to screen patients with specific allele variants beforehand. Theoretically, biomarkers could be learned to predict the drug toxicity for each individual patient, when given enough training datasets. One proof-of-concept example is from the DREAM challenge, in which by integrating genetic profiles of cell lines with the compound chemical information, the in silico methods could predict cytotoxicity phenotype [84], largely supporting the feasibility of prediction of individualized drug toxicity [85]. GWAS as a hypothesis-free method has successfully identified novel genes that are responsible for drug response or drug-induced toxicity [86]. For example, through GWA study, a genetic variant on the TCL1A gene was found to induce musculoskeletal adverse events, revealing the involvement of cytokine receptor genes in the inflammatory response [87]. A similar study found the significant association between the genetic variants on the CACNB4 gene and the drug-induced alopecia in breast cancer, suggesting the mechanism of the pathogenesis of alopecia involving ion channels [88].