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Thiopurine Methyltransferase Activity (thiopurine + methyltransferase_activity)
Selected AbstractsMercaptopurine treatment should be considered in azathioprine intolerant patients with inflammatory bowel diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2009U. HINDORF Summary Background, Adverse drug reactions are a significant reason for therapeutic failure during thiopurine treatment of inflammatory bowel disease. Some smaller series in this patient population have shown that a switch to mercaptopurine may be successful in many cases of azathioprine intolerance. Aim, To assess the long-term outcome of mercaptopurine treatment in a large patient population with azathioprine intolerance. Methods, We identified 135 patients (74 women; median age 40 years) with Crohn's disease (n = 88) or ulcerative colitis (n = 47) and reviewed their medical records. Results, A total of 70 patients (52%) tolerated mercaptopurine and were followed up for 736 (362,1080) days; 65 patients discontinued mercaptopurine due to adverse events after 25 (8,92) days. Mercaptopurine was tolerated in 71% (12/17) with hepatotoxicity and in 68% (13/19) with arthralgia/myalgia during azathioprine treatment. Previous abdominal surgery was more common in mercaptopurine intolerant patients [39/65 (60%) vs. 27/70 (39%); P = 0.02] and thiopurine methyltransferase activity was higher in mercaptopurine tolerant patients than in mercaptopurine intolerant patients [13.2 (11.4,15.3) vs. 11.8 (9.6,14.2) U/mL red blood cells; P = 0.04; n = 81]. Conclusions, A trial of mercaptopurine should be considered in azathioprine intolerance, as half of the patients tolerate a switch to mercaptopurine. Patients with hepatotoxicity or arthralgia/myalgia during azathioprine treatment might benefit more often than those with other types of adverse events. [source] Adverse events leading to modification of therapy in a large cohort of patients with inflammatory bowel diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2006U. HINDORF Summary Background Adverse events leading to discontinuation or dose reduction of thiopurine therapy occur in 9,28% of patients with inflammatory bowel disease. Aims To evaluate the influence of thiopurine methyltransferase status and thiopurine metabolites in a large patient population for the risk of developing adverse event. Methods Three hundred and sixty-four patients with inflammatory bowel disease and present or previous thiopurine therapy were identified from a local database. Results The adverse event observed in 124 patients (34%) were more common in adults than children (40% vs. 15%; P < 0.001) and in low to intermediate (,9.0 U/mL red blood cell) than normal thiopurine methyltransferase activity (P = 0.02). Myelotoxicity developed later than other types of adverse event. An increased frequency of adverse event was observed in patients with tioguanine (thioguanine) nucleotide above 400 or methylated thioinosine monophosphate above 11 450 pmol/8 × 108 red blood cell. A shift to mercaptopurine was successful in 48% of azathioprine-intolerant patients and in all cases of azathioprine-induced myalgia or arthralgia. Conclusions A pre-treatment determination of thiopurine methyltransferase status might be appropriate as patients with low to intermediate thiopurine methyltransferase activity are more prone to develop an adverse event; determination of metabolite levels can be useful in the case of an adverse event. Mercaptopurine therapy should be considered in azathioprine-intolerant patients. [source] Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurineALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2005M. P. SPARROW Summary Background :,Many non-responders to azathioprine or mercaptopurine (6-mercaptopurine) have high normal thiopurine methyltransferase activity and preferentially metabolize mercaptopurine to produce 6-methylmercaptopurine instead of the active 6-tioguanine (6-tioguanine) metabolites. Aim :,To describe the use of allopurinol in mercaptopurine/azathioprine non-responders to deliberately shunt metabolism of mercaptopurine towards 6-tioguanine. Methods :,Fifteen thiopurine non-responders whose metabolites demonstrated preferential metabolism towards 6-methylmercaptopurine are described. Subjects were commenced on allopurinol 100 mg po daily and mercaptopurine/azathioprine was reduced to 25,50% of the original dose. Patients were followed clinically and with serial 6-tioguanine and 6-methylmercaptopurine metabolite measurements. Results :,After initiating allopurinol, 6-tioguanine levels increased from a mean of 185.73 ± 17.7 to 385.4 ± 41.5 pmol/8 × 108 red blood cells (P < 0.001), while 6-methylmercaptopurine decreased from a mean of 10 380 ± 1245 to 1732 ± 502 pmol/8 × 108 RBCs (P < 0.001). Allopurinol led to a decrease in white blood cell from a mean of 8.28 ± 0.95 to 6.1 ± 0.82 × 108/L (P = 0.01). Conclusions :,The addition of allopurinol to thiopurine non-responders with preferential shunting to 6-methylmercaptopurine metabolites appears to be an effective means to shift metabolism towards 6-tioguanine. [source] Interaction between azathioprine and aminosalicylates: an in vivo study in patients with Crohn's diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2002O. Dewit Background: The inhibition of thiopurine methyltransferase activity, one of the enzymes responsible for azathioprine metabolism, by aminosalicylates has been described in an in vitro study. This could result in a higher risk of bone marrow depression when using the two drugs together. Aim: To investigate the in vivo interaction between azathioprine and aminosalicylates in quiescent Crohn's disease by measuring 6-thioguanine nucleotide levels, thiopurine methyltransferase activity and the plasma levels of the acetylated metabolite of 5-aminosalicylic acid. Methods: Sixteen patients taking a stable dose of azathioprine, plus sulfasalazine or mesalazine, were enrolled and completed the study. They were not taking any drugs interfering with azathioprine metabolism. Four visits every 4 weeks were held over a 3-month period. Aminosalicylate administration was withdrawn after the second visit. At each visit, the blood cell count, inflammatory parameters, levels of 6-thioguanine nucleotide and the acetylated metabolite of 5-aminosalicylic acid and thiopurine methyltransferase activity were determined. Results: After aminosalicylate withdrawal, mean 6-thioguanine nucleotide levels decreased significantly from 148 pmol (57,357 pmol) to 132 pmol (56,247 pmol) per 8 × 108 red blood cells (P=0.027), without significant changes in thiopurine methyltransferase activity or biological parameters. Conclusions: This in vivo study favours the existence of an interaction between azathioprine and aminosalicylates through a mechanism which remains unclear. This drug,drug interaction should be taken into account when using azathioprine and aminosalicylates simultaneously. [source] Human thiopurine methyltransferase activity varies with red blood cell ageBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2001L. Lennard Aims, Inherited differences in thiopurine methyltransferase (TPMT) activity are an important factor in the wide interindividual variations observed in the clinical response to thiopurine chemotherapy. The aim of this study was to establish a population range for red blood cell (RBC) TPMT activity in children with acute lymphoblastic leukaemia (ALL) at disease diagnosis. An additional aim was to investigate factors that can influence TPMT activity within the RBC. Methods,Blood samples were collected from children with ALL at disease diagnosis, prior to any blood transfusions, as part of the nationwide UK MRC ALL97 therapeutic trial. RBC TPMT activity was measured by h.p.l.c. RBCs were age-fractionated on Percoll density gradients. Results,Pretreatment blood samples were received from 570 children within 3 days of venepuncture. TPMT activities at disease diagnosis ranged from 1.6 to 23.6 units/ml RBCs (median 7.9) compared with 0.654,18.8 units (median 12.9), in 111 healthy control children (median difference 4.5 units, 95% CI 3.9, 5.1 units, P < 0.001). A TPMT quality control sample, aliquots of which were assayed in 60 analytical runs over a 12 month period, contained a median of 11.98 units with a CV of 11.6%. Seven children had their RBCs age-fractionated on density gradients. TPMT activities in the top gradient (young cells) ranged from 4.2 to 14.1 units (median 7.5) and in the bottom gradient (old cells) 1.5,12.6 units (median 4.7 units), median difference 2.3 units, 95% CI 0.7, 4.1, P = 0.035. Conclusions,Circulating RBCs do not constitute a homogeneous population. They have a life span of around 120 days and during that time undergo a progressive ageing process. The anaemia of ALL is due to deficient RBC production. The results of this study indicate that RBC TPMT activities are significantly lower in children with ALL at disease diagnosis. This may be due, at least in part, to a relative excess of older RBCs. [source] | ||||||||||