Prospective study of the effects of concomitant medications on thiopurine metabolism in inflammatory bowel disease

Sostegni, R.; Canaparo, Roberto; Serpe, Loredana; Lavagna, A.; Crocellà, L.; Castagno, Franco; Vernetto, Annalisa; Rigazio, C.; Ercole, E.; D’Antico, Sergio; Pera, A.; Zara, Gian Paolo; Rocca, Rodolfo

doi:10.1111/j.1365-2036.2009.04106.x

Cited by 15 publications

(18 citation statements)

References 53 publications

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“…Finally, some authors have suggested a synergistic effect of aminosalicylates or infliximab on thiopurine metabolite RBC levels 38, 39 ; we found no influence on metabolite RBC levels by any of those drugs. Even though we could not analyse the impact of different doses, our results regarding the impact of aminosalicylates on thiopurine metabolism is consistent with previous studies 8, 40 …”

Section: Discussionsupporting

confidence: 91%

Thiopurine methyl-transferase activity and azathioprine metabolite concentrations do not predict clinical outcome in thiopurine-treated inflammatory bowel disease patients

González-Lama

Bermejo²,

López-Sanromán

et al. 2011

Alimentary Pharmacology &Amp; Therapeutics

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Aliment Pharmacol Ther 2011; 34: 544–554 Summary Background Low thiopurine‐methyl‐transferase (TPMT) activity and high 6‐thioguanine‐nucleotide (6TGN) concentrations have been linked to therapeutic success in inflammatory bowel disease patients treated with thiopurines; however, this has not been implemented in clinical practice. Aim To identify a therapeutic threshold value for TPMT or 6TGN concentrations, and their capability to predict treatment safety and efficacy. Methods Prospective multicentre study including steroid‐resistant/dependent patients starting thiopurines. The TPMT activity was determined at inclusion (>5 U/mL required). Azathioprine metabolites [6TGN, 6‐methyl‐mercaptopurine ribonucleotides (6MMP), and 6TGN/6MMP and 6TGN/TPMT ratios] were periodically monitored during steroid tapering and after withdrawal for 6 months or until a new flare occurred. Results A total of 113 patients were analysed (62% clinical response). Areas under the receiver operating characteristic (ROC) curve (AUC) relating clinical response and metabolite levels at 2, 4 and 6 months after steroid withdrawal were less than 0.7. The AUCs relating final response and initial TPMT activity or metabolite concentrations at 2, 4, 8 and 16 weeks after starting thiopurines were less than 0.7. No cut‐off point with worthwhile sensitivity/specificity was found. Eight (7%) patients developed thiopurine‐related toxicity that could not be linked to TPMT activity or 6TGN levels. Conclusions Our results do not support determination of TPMT activity or 6TGN concentrations to predict treatment outcome, and no useful serum metabolites threshold value to adjust the drug’s dose was identified.

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Section: Discussionsupporting

confidence: 91%

Thiopurine methyl-transferase activity and azathioprine metabolite concentrations do not predict clinical outcome in thiopurine-treated inflammatory bowel disease patients

González-Lama

Bermejo²,

López-Sanromán

et al. 2011

Alimentary Pharmacology &Amp; Therapeutics

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“…Likewise, no differences were found in 6-thioguanine and 6-methylmercaptopurine levels between the two patient groups [Daperno et al 2009]. These results differ from those recorded in other intervention studies in which the addition of 5-ASA to stable thiopurine doses was found to significantly increase the 6-thioguanine levels [de Boer et al 2007;Gilissen et al 2005].…”

Section: Introductioncontrasting

confidence: 56%

Usefulness of salicylate and thiopurine coprescription in steroid-dependent ulcerative colitis and withdrawal strategies

Bermejo

Gisbert

2010

Therapeutic Advances in Chronic Disease

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5-aminosalicylic acid (5-ASA) and thiopurines (azathioprine and mercaptopurine) are the most common drugs used as a maintenance treatment for ulcerative colitis. A considerable proportion of these patients develop corticosteroid dependency, and thiopurines are the standard treatment in this scenario. Dual prescriptions of both thiopurines and 5-ASA are common practice in steroid-dependent ulcerative colitis, in an attempt to optimize the efficacy of therapy. On the one hand, the potential protective role of 5-ASA against colorectal cancer argues in favour of prescription of both medications. The possible synergism between the two drugs, because of the inhibition of thiopurine methyltransferase (TPMT) enzyme activity by 5-ASA, has been postulated as another justification for dual prescription. However, existing evidence does not support that this combined strategy is superior to monotherapy with thiopurines. On the other hand, in patients showing prolonged disease remission, the possibility of discontinuing maintenance treatment can be considered on an individualized basis. The high frequency of relapses after thiopurine withdrawal should always be taken into account, but the potential adverse effects of the medication also need to be considered. A properly indicated treatment with thiopurines may need to be continued for life in many patients.

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“…Not all studies have reproduced these results. In a cross‐sectional study of 183 consecutive IBD patients no significant differences were noted in 6‐TGN or 6‐MMP levels or TPMT activity between thiopurine patients receiving, or not receiving, concomitant aminosalicylates ( P > 0.05) 41. It would seem prudent to conclude that while TPMT inhibition by aminosalicylates may occur, the clinical significance of this interaction is minimal.…”

Section: How To Optimize Thiopurine Therapy?mentioning

confidence: 92%

Biogenic amine synthesis and uptake in rodent taste buds

Dvoryanchikov

Tomchik

Chaudhari

2007

J of Comparative Neurology

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Although adenosine triphosphate (ATP) is known to be an afferent transmitter in the peripheral taste system, serotonin (5-HT) and norepinephrine (NE) have also been proposed as candidate neurotransmitters and have been detected immunocytochemically in mammalian taste cells. To understand the significance of biogenic amines in taste, we evaluated the ability of taste cells to synthesize, transport, and package 5-HT and NE. We show by reverse transcriptase-polymerase chain reaction and immunofluorescence microscopy that the enzymes for 5-HT synthesis, tryptophan hydroxylase (TPH) and aromatic amino acid decarboxylase (AADC) are expressed in taste cells. In contrast, enzymes necessary for NE synthesis, tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) are absent. Both TH and DBH are expressed in nerve fibers that penetrate taste buds. Taste buds also robustly express plasma membrane transporters for 5-HT and NE. Within the taste bud NET, a specific NE transporter, is expressed in some presynaptic (type III) and some glial-like (type I) cells but not in receptor (type II) cells. By using enzyme immunoassay, we show uptake of NE, probably through NET in taste epithelium. Proteins involved in inactivating and packaging NE, including catechol-O-methyltransferase (COMT), monoamine oxidase-A (MAO-A), vesicular monoamine transporter (VMAT1,2) and chromogranin A (ChrgA), are also expressed in taste buds. Within the taste bud, ChrgA is found only in presynaptic cells and may account for dense-cored vesicles previously seen in some taste cells. In summary, we postulate that aminergic presynaptic taste cells synthesize only 5-HT, whereas NE (perhaps secreted by sympathetic fibers) may be concentrated and repackaged for secretion.

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Prospective study of the effects of concomitant medications on thiopurine metabolism in inflammatory bowel disease

Abstract: SUMMARY BackgroundThiopurines are increasingly used in the treatment of inflammatory bowel disease (IBD), being the most common immunosuppressive therapy; however, potentially harmful interactions between thiopurines and other drugs (especially 5-aminosalicylic acid, 5-ASA) were described.

Cited by 15 publications

References 53 publications

Thiopurine methyl-transferase activity and azathioprine metabolite concentrations do not predict clinical outcome in thiopurine-treated inflammatory bowel disease patients

Thiopurine methyl-transferase activity and azathioprine metabolite concentrations do not predict clinical outcome in thiopurine-treated inflammatory bowel disease patients

Usefulness of salicylate and thiopurine coprescription in steroid-dependent ulcerative colitis and withdrawal strategies

Biogenic amine synthesis and uptake in rodent taste buds

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