Thiopurine S-methyltransferase and Pemphigus Vulgaris: A Phenotype-Genotype Study

Mokhtari, Maral; Mostanbet, Farzaneh; Fard, Saideh Nekooee; Shekarkhar, Golsa; Sepaskhah, Mozhdeh; Sadati, Maryam Sadat

doi:10.30699/ijp.2020.121365.2320

Cited by 2 publications

(3 citation statements)

References 28 publications

(73 reference statements)

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“…TPMT ∗ 2, TPMT ∗ 3A, TPMT ∗ 3B, and TPMT ∗ 3C are inactivating alleles that explain 80% to 95% of individuals with lower TPMT activity. The most common subtypes such as TPMT ∗ 3A and TPMT ∗ 3C showed less frequency in our population according to different studies [ 38 , 39 ]. Furthermore, results of previous Iranian studies revealed that there were no signs of both defective alleles in the population [ 38 ].…”

Section: Discussionmentioning

confidence: 82%

“…Furthermore, results of previous Iranian studies revealed that there were no signs of both defective alleles in the population [ 38 ]. A study on Pemphigus Vulgaris patients taking AZA showed no TPMT ∗ 2 or TPMT ∗ 3C mutant alleles and none of the subjects developed hepatotoxicity and bone marrow suppression [ 39 ]. Therefore, we carefully monitored the patients' blood counts every month, and if signs of reduction in blood counts were observed, the TPMT test was ordered.…”

Section: Discussionmentioning

confidence: 99%

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Oral Pemphigus Vulgaris Treatment with Corticosteroids and Azathioprine: A Long-Term Study in Shiraz, Iran

Davarmanesh

Zahed

Sookhakian

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Background Treating oral mucosal lesions of Pemphigus Vulgaris (PV) disease is usually challenging for clinicians. We studied the treatment outcomes of the oral PV patients referred to the Oral Medicine Department of Shiraz University of Medical Sciences from 2004 to 2018. Methods The medical records of 54 oral PV patients with histopathological confirmation who were treated by a single protocol were studied. The protocol consisted of initial treatment with 1 mg/kg/day of oral prednisolone for all patients. After 4–6 weeks, all patients were prescribed 40 mg of prednisolone. If lesion recovery was not observed or new lesions had developed, adjuvant therapy (maximum dose of 200 mg per day of Azathioprine (AZA)) was initiated anytime during the treatment. The oral prednisolone dosage was gradually tapered to 5 mg/alternate day in 9 months. Results 47 patients were included in the study. 34.04% were male and 65.96% were female with a mean age of 41.83 ± 12.520. The mean follow-up period was 50.806 ± 44.417 months (over 4 years). The severity of oral involvement was mild in 21.27%, moderate in 36.17%, and severe in 42.6%. During treatment, all patients except one experienced complete remission. The mean time to achieve complete remission was 150.39 ± 224.075 days. Most of the patients experienced relapse due to self-discontinuation of treatment. 55% had complete remission and 43% were in partial remission at the last follow-up session. In 65.96% of patients, treatment-associated side effects were observed. The patients treated with prednisolone alone had significantly more side effects than those using AZA as an adjuvant (80% vs 50%, respectively; P =0.030). The mean duration of follow-ups was longer for patients with side effects ( P < 0.01). Topical corticosteroids were used for all patients sometime during the treatment. No deaths were recorded. Conclusion Prescribing low-dose prednisolone and adding AZA in nonresponding cases has good clinical outcomes for the treatment of oral lesions of PV. Adjuvant therapy can avoid the increase in corticosteroid dosage and side effects. The treatment method described in this study can be a helpful guide for clinicians, especially when other immunosuppressive drugs are not available.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Oral Pemphigus Vulgaris Treatment with Corticosteroids and Azathioprine: A Long-Term Study in Shiraz, Iran

Davarmanesh

Zahed

Sookhakian

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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“…Actually, TPMT phenotype testing is fairly common in some countries ( Fargher et al, 2007 ; Weitzel et al, 2018 ). However, it is worth noting that TPMT enzyme activity is usually measured in fresh red blood cells directly ( Mokhtari et al, 2020 ), or consumes a longer turnaround test time ( Weitzel et al, 2018 ). Moreover, in patients who have received blood transfusions recently or in leukemia patients, because of atypical hematopoiesis, the result could not reflect the true enzymatic activity ( Mokhtari et al, 2020 ).…”

Section: Pharmacogenetics Of Thiopurinesmentioning

confidence: 99%

Optimizing thiopurine therapy in children with acute lymphoblastic leukemia: A promising “MINT” sequencing strategy and therapeutic “DNA-TG” monitoring

Guo

Zhao²,

Dong³

et al. 2022

Front. Pharmacol.

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Thiopurines, including thioguanine (TG), 6-mercaptopurine (6-MP), and azathioprine (AZA), are extensively used in clinical practice in children with acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases. However, the common adverse effects caused by myelosuppression and hepatotoxicity limit their application. Metabolizing enzymes such as thiopurine S-methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), inosine triphosphate pyrophosphohydrolase (ITPA), and drug transporters like multidrug resistance-associated protein 4 (MRP4) have been reported to mediate the metabolism and transportation of thiopurine drugs. Hence, the single nucleotide polymorphisms (SNPs) in those genes could theoretically affect the pharmacokinetics and pharmacological effects of these drugs, and might also become one of the determinants of clinical efficacy and adverse effects. Moreover, long-term clinical practices have confirmed that thiopurine-related adverse reactions are associated with the systemic concentrations of their active metabolites. In this review, we mainly summarized the pharmacogenetic studies of thiopurine drugs. We also evaluated the therapeutic drug monitoring (TDM) research studies and focused on those active metabolites, hoping to continuously improve monitoring strategies for thiopurine therapy to maximize therapeutic efficacy and minimize the adverse effects or toxicity. We proposed that tailoring thiopurine dosing based on MRP4, ITPA, NUDT15, and TMPT genotypes, defined as “MINT” panel sequencing strategy, might contribute toward improving the efficacy and safety of thiopurines. Moreover, the DNA-incorporated thioguanine nucleotide (DNA-TG) metabolite level was more suitable for red cell 6-thioguanine nucleotide (6-TGNs) monitoring, which can better predict the efficacy and safety of thiopurines. Integrating the panel “MINT” sequencing strategy with therapeutic “DNA-TG” monitoring would offer a new insight into the precision thiopurine therapy for pediatric acute lymphoblastic leukemia patients.

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Thiopurine S-methyltransferase and Pemphigus Vulgaris: A Phenotype-Genotype Study

Cited by 2 publications

References 28 publications

Oral Pemphigus Vulgaris Treatment with Corticosteroids and Azathioprine: A Long-Term Study in Shiraz, Iran

Oral Pemphigus Vulgaris Treatment with Corticosteroids and Azathioprine: A Long-Term Study in Shiraz, Iran

Optimizing thiopurine therapy in children with acute lymphoblastic leukemia: A promising “MINT” sequencing strategy and therapeutic “DNA-TG” monitoring

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