Background: Firm recommendations about the way thiopurine drugs are introduced and the use of thiopurine methyltransferase (TPMT) and metabolite measurements during treatment in inflammatory bowel disease (IBD) are lacking. Aim: To evaluate pharmacokinetics and tolerance after initiation of thiopurine treatment with a fixed dosing schedule in patients with IBD. Patients: 60 consecutive patients with Crohn's disease (n = 33) or ulcerative colitis (n = 27) were included in a 20 week open, prospective study. Methods: Thiopurine treatment was introduced using a predefined dose escalation schedule, reaching a daily target dose at week 3 of 2.5 mg azathioprine or 1.25 mg 6-mercaptopurine per kg body weight. TPMT and ITPA genotypes, TPMT activity, TPMT gene expression, and thiopurine metabolites were determined. Clinical outcome and occurrence of adverse events were monitored. Results: 27 patients completed the study per protocol, while 33 were withdrawn (early protocol violation (n = 5), TPMT deficiency (n = 1), thiopurine related adverse events (n = 27)); 67% of patients with adverse events tolerated long term treatment on a lower dose (median 1.32 mg azathioprine/kg body weight). TPMT activity did not change during the 20 week course of the study but a significant decrease in TPMT gene expression was found (TPMT/huCYC ratio; p = 0.02). Patients with meTIMP concentrations .11 450 pmol/8610 8 red blood cells during steady state at week 5 had an increased risk of developing myelotoxicity (odds ratio = 45.0; p = 0.015). Conclusions: After initiation of thiopurine treatment using a fixed dosing schedule, no general induction of TPMT enzyme activity occurred, though TPMT gene expression decreased. The development of different types of toxicity was unpredictable, but we found that measurement of meTIMP early in the steady state phase helped to identify patients at risk of developing myelotoxicity.

SUMMARY BackgroundAdverse events leading to discontinuation or dose reduction of thiopurine therapy occur in 9-28% of patients with inflammatory bowel disease.

Abstract-Thrombosis and inflammation involve complex platelet-leukocyte interaction, the details of which are not fully elucidated. Therefore, we investigated cross talk between platelets and leukocytes in whole blood, under the following physiological conditions: at 37°C, with normal calcium concentrations, and with shear force. Platelet P-selectin and leukocyte CD11b expression were used to monitor platelet and leukocyte activation, respectively, and platelet-leukocyte aggregation (PLA) was analyzed. The leukocyte-specific agonist N-formyl-methionyl-leucyl-phenylalanine (10 Ϫ6 mol/L) increased P-selectin-positive platelets from 2.5Ϯ0.1% to 5.1Ϯ0.6% (PϽ0.05). The increase was inhibited by either the platelet-activating factor (PAF) antagonist SR27417, the superoxide anion scavenger superoxide dismutase, the 5-lipoxygenase inhibitor Zileuton, or the 5-lipoxygenase-activating protein inhibitor MK-886, suggesting the involvement of PAF, superoxide anion, and 5-lipoxygenase products in leukocyte-induced platelet activation. The platelet-specific agonist collagen (1 g/mL) increased leukocyte CD11b expression from 2.

Recurrences of erysipelas are especially prevalent in patients suffering from local impairment of circulation and intervention might thus be of benefit. Therefore a prospective, randomized, open study was undertaken to evaluate whether daily antibiotic prophylaxis would reduce the risk of recurrence. Patients with venous insufficiency or lymphatic congestion who had suffered two or more episodes of erysipelas during the previous 3 years and were admitted to the Infectious Disease Department at Roslagstull Hospital, Stockholm, Sweden, between November 1988 and November 1991 were included. Fourty patients, 20 on prophylaxis and 20 controls were followed according to a life table analysis during a median time of 15 months. Phenoxymethylpenicillin was prescribed as daily prophylaxis (while erythromycin was given to patients allergic to penicillin). Recurrences of erysipelas appeared to be reduced by daily antibiotic prophylaxis but the effect was not dramatic (p = 0.06). Only in patients with a high recurrence rate continuous antibiotic prophylaxis against erysipelas is indicated.