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The Precision Medicine Approach in Oncology
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Genetic polymorphisms that affect TPMP activity correlate well with variations in sensitivity and toxicity toward purine antimetabolites within individuals, and approximately 1 in 300 individuals is deficient in the enzyme. Individuals with low or intermediate activity are at risk of ADRs unless the drug dose is reduced to approximately 10% of the standard dose. Patients with low activity (~10% prevalence) or especially absent activity (prevalence ~0.3%) are at a heightened risk of drug-induced bone marrow toxicity due to accumulation of the unmetabolized drug. One study has shown that approximately 5% of all thiopurine therapies fail due to toxicity, and this intolerant group can be predicted by routine measurement of TPMT activity.
Gastrointestinal disease
Published in Catherine Nelson-Piercy, Handbook of Obstetric Medicine, 2020
Combining allopurinol with a lower dose of thiopurine can improve clinical efficacy and bypass some adverse reactions associated with thiopurine monotherapy. Data on allopurinol in pregnancy are scarce, but no adverse effects are reported.
Mucous membrane pemphigoid
Published in Biju Vasudevan, Rajesh Verma, Dermatological Emergencies, 2019
Dipankar De, Sheetanshu Kumar, Sanjeev Handa
Azathioprine has also been successfully used in MMP [23]. It usually takes around 8–12 weeks to produce an effect. Before initiating therapy, thiopurine S-methyltransferase levels should be checked and dose decided accordingly ranging from 1 to 4 mg/kg/day. Side effects include bone marrow suppression, gastrointestinal intolerance, and hepatotoxicity.
Prevalence of polymorphisms in thiopurine metabolism and association with adverse outcomes: a South Asian region-specific systematic review and meta-analysis
Published in Expert Review of Clinical Pharmacology, 2021
Anuraag Jena, Daya Krishna Jha, Praveen Kumar-M, Kripa Shanker Kasudhan, Ankit Kumar, Dhruv Sarwal, Shubhra Mishra, Anupam Kumar Singh, Prateek Bhatia, Amol Patil, Vishal Sharma
This meta-analysis on TPMT and NUDT15 polymorphisms in the South Asian population illustrated a high prevalence of NUDT15 polymorphisms (16.5%) in this population as compared to TPMT polymorphisms (4.57%). Among the patients who develop leukopenia on thiopurine therapy, the pooled prevalence of NUDT15 polymorphism was higher (49%) as compared to TPMT polymorphisms (9.47%). Further, the odds of developing an adverse effect of thiopurine were higher in the NUDT15 polymorphism group although both TPMT and NUDT15 polymorphism group had higher odds as compared to the wild type. The results suggest the need for testing for NUDT15 over and above TPMT polymorphisms, if preemptive testing is being considered, in the South Asian populations. This could help avoid severe adverse events with thiopurine therapy and guide dosing of the thiopurines.
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].
Recent approaches to gout drug discovery: an update
Published in Expert Opinion on Drug Discovery, 2020
Naoyuki Otani, Motoshi Ouchi, Hideo Kudo, Shuichi Tsuruoka, Ichiro Hisatome, Naohiko Anzai
Allopurinol is associated with several adverse effects, including gastrointestinal effects, rash, and Stevens-Johnson’s syndrome [14], as well as the rare but potentially fatal adverse event – allopurinol hypersensitivity syndrome (AHS). AHS is characterized by rash (e.g., Stevens‐Johnson syndrome, toxic epidermal necrolysis), eosinophilia, leukocytosis, fever, increased risk of hepatitis, and renal failure [15]. Risk factors for the development of AHS include the HLA–B*5801 genotype. The prevalence of HLA-B*5801 is as low as 1–2% in Japanese people, but as high as 20–30% in Chinese people; thus, adverse reactions are also associated with a genetic background [16]. Caution should be applied for using allopurinol with other drugs due to drug interactions, because allopurinol is prone to causing aplastic anemia when used in combination with drugs that cause bone marrow suppression, such as cyclophosphamide. Also, the interaction between allopurinol and azathioprine, a thiopurine drug, and its metabolite, 6‐mercaptopurine (6‐MP), is among the clinically significant drug interactions known. This combination of drugs can result in significant myelosuppression, and in some instances, death. In summary, the XOR inhibitor allopurinol, which is reportedly limited to use in patients with renal failure and due to drug interactions, has long been the basis for managing hyperuricemia.