Relationship Between Thiopurine S-Methyltransferase Genotype/Phenotype and 6-Thioguanine Nucleotide Levels in 316 Patients With Inflammatory Bowel Disease on 6-Thioguanine.

BACKGROUND: In inflammatory bowel disease (IBD), conventional thiopurine users cease treatment in 60% of cases within 5 years, mostly because of adverse events or nonresponse. In this study, the authors aimed to investigate the role of 6-thioguanine nucleotide (TGN) measurements, geno/phenotyping of thiopurine S-methyltransferase (TPMT), and their mutual relationship with TG therapy in IBD. METHODS: An international retrospective, multicenter cohort study was performed at 4 centers in the Netherlands (Máxima Medical Centre) and the United Kingdom (Guy's and St. Thomas' Hospital, Queen Elizabeth Hospital, and East Surrey Hospital). RESULTS: Overall, 526 6-TGN measurements were performed in 316 patients with IBD. The median daily dosage of TG was 20 mg/d (range 10-40 mg/d), and the median duration of TG use was 21.1 months (SD, 28.0). In total, 129 patients (40.8%) had a known TPMT status. In the variant-type and wild-type TPMT genotype metabolism groups, median 6-TGN values were 1126 [interquartile range (IQR) 948-1562] and 467.5 pmol/8 × 10E8 red blood cells (RBCs) (IQR 334-593). A significant difference was observed between the 2 groups (P = 0.0001, t test). For TPMT phenotypes, in the slow, fast, and normal metabolism groups, the median 6-TGN values were 772.0 (IQR 459-1724), 296.0 (IQR 200-705), and 774.5 pmol/8 × 10E8 RBCs (IQR 500.5-981.5), with a significant difference observed between groups (P < 0.001, analysis of variance). CONCLUSIONS: Our findings indicated that TPMT measurements at TG initiation can be useful but are not necessary for daily practice. TPMT genotypes and phenotypes are both associated with significant differences in 6-TGN levels between metabolic groups. However, the advantage of TG remains that RBC 6-TGN measurements are not crucial to monitor treatments in patients with IBD because these measurements did not correlate with laboratory result abnormalities. This presents as a major advantage in countries where patients cannot access these diagnostic tests.

Efficacy, safety and drug survival of thioguanine as maintenance treatment for inflammatory bowel disease: a retrospective multi-centre study in the United Kingdom.

BACKGROUND: Thioguanine (TG) is a thiopurine which has been used for patients with inflammatory bowel disease (IBD), who have failed azathioprine (AZA) or mercaptopurine (MP) due to adverse events or suboptimal response. Its widespread use has been hampered due to concerns about nodular regenerative hyperplasia (NRH) of the liver. The aim of this study was to investigate the long-term efficacy and safety of low-dose TG therapy in IBD patients failing AZA and MP. METHODS: A retrospective multicentre study was performed in IBD patients who failed prior treatment with conventional thiopurines with or without following immunomodulation (thiopurine-allopurinol, biologicals, methotrexate, tacrolimus) and were subsequently treated with TG as rescue monotherapy between 2003 and 2019 at three hospitals in the United Kingdom. Clinical response, adverse events, laboratory results, imaging and liver biopsies were retrospectively collected. RESULTS: A total of 193 patients (57% female and 64% Crohn's disease) were included, with a median daily TG dose of 20 mg (range: 20-40 mg), a median treatment duration of 23 months (IQR 10-47) and a median follow-up of 36 months (IQR 22-53). The clinical response rate at 12 months was 65 and 54% remained on TG until the end of follow-up. Adverse events consisted primarily of elevated liver tests (6%), myelotoxicity (7%) and rash (5%). NRH was histologically diagnosed in two patients and two other patients (1%) developed non-cirrhotic portal hypertension. The median 6-TGN and TPMT levels were 953 pmol/8 × 105 RBC (IQR 145-1761) and 47 mu/L (IQR 34.5-96). CONCLUSIONS: Long-term follow-up suggests that TG can be an effective and well-tolerated therapy in more than half of difficult-to-treat and multi-therapy failing IBD patients. Findings of this study indicate that TG can be used safely and the occurrence of hepatotoxicity was low. The incidence rate of NRH was within the background incidence.

Midazolam with meperidine or fentanyl for colonoscopy: results of a randomized trial.

BACKGROUND: A combination of midazolam and opioid is usually used to achieve sedation and analgesia during colonoscopy. Two commonly used opioids are meperidine and fentanyl, but few studies have compared their efficacy. OBJECTIVE: This randomized trial aimed to compare the efficacy and recovery time of 2 sedation regimens consisting of midazolam in combination with either meperidine or fentanyl. DESIGN, SETTING, AND PATIENTS: A total of 300 consecutive, unselected adults attending outpatient colonoscopy at a District General Hospital were enrolled with informed consent and randomized to receive midazolam with meperidine or fentanyl. Data for procedure times, perceived discomfort (according to standard 100-mm visual analog scales [VAS]), and recovery time were collected. Patients and all endoscopy staff directly involved with the procedure were blinded to the regimen used. MAIN OUTCOME MEASUREMENTS: Primary: patients' experience of pain (postrecovery VAS score); secondary: recovery time. RESULTS: A total of 287 patients (150 female, mean [SD] age 54 [17] years) were studied. Recovery time (in minutes) was significantly shorter in patients receiving fentanyl (n = 138) than in those receiving meperidine (n = 149, mean +/- SE: 13.7 +/- 1.8 vs 18.7 +/- 1.7, P = .03), whereas there was no difference in the patients', endoscopists', or nurses' perception of pain during the procedure between the 2 groups. Both groups received a median dose of 3 mg of midazolam (range 2-5 mg). In patients receiving lower doses (2-2.5 and 3-3.5 mg), recovery times were significantly faster with fentanyl (P < .01 and <.05, respectively), whereas at higher doses of midazolam (> or =4 mg) there was no difference between the 2 groups. LIMITATIONS: The use of VAS scores and nurse assessment of recovery time were chosen in this study because, despite their subjectivity, these measures were felt to most closely reflect true clinical practice. CONCLUSIONS: The use of fentanyl in combination with low-dose midazolam results in significantly faster recovery from sedation compared with meperidine, without any apparent loss of analgesic effect.

The contribution of deleterious DPYD gene sequence variants to fluoropyrimidine toxicity in British cancer patients.

PURPOSE: The fluoropyrimidines have been extensively used for almost five decade worldwide for the treatment of solid cancers. However, severe toxicity is a major clinical problem and has been reported in association with deleterious sequence variants in dihydropyrimidine dehydrogenase (DPD) coding-gene (DPYD), causing DPD deficiency. Genetic DPD deficiency has previously been considered to be insignificant in the British population. The study aim was to assess the contribution of deleterious DPYD sequence variants to fluoropyrimidine toxicity amongst British cancer patients. METHODS: Sequencing of the coding region of DPYD was undertaken in 47 patients (27 female, mean age 61 years), mainly with GI malignancy, experiencing grade 3 or 4 toxicity on fluoropyrimidines according to CTCAE criteria. RESULTS: Myelotoxicity (37.5%) and diarrhoea (37.5%) were the most frequent toxicities followed by mucositis (19.6%), hand-foot syndrome (3.6%) and neurotoxicity (1.8%). 4 of 47 (8.5%) patients carried the 1905+1G>A splice site variant. All 4 cases were female and 3 of 4 suffered severe diarrhoea. A further five cases carried other sequence variants (2846A>T n = 4, 1679T>G n = 1). In total, 9 (19%) patients carried deficiency associated DPYD sequence variants. CONCLUSIONS: Contrary to previous estimates for a UK population, genetic DPD deficiency accounts for around 19% of cases of severe fluoropyrimidine toxicity. The influence of DPD deficiency is such that toxicity can be avoided by prior testing and appropriate 5-FU dose/regimen alteration.