Therapeutic drug monitoring in patients with inflammatory bowel disease and established azathioprine therapy.

BACKGROUND AND OBJECTIVE: Azathioprine is widely used in the treatment of corticosteroid-dependent and refractory inflammatory bowel disease (IBD). The efficacy of this treatment is based on the production of 6-thioguanine nucleotides, but extremely elevated levels may cause bone marrow suppression. Other azathioprine metabolites, 6-methylmercaptopurine ribonucleotides, are associated with hepatotoxicity. Therapeutic drug monitoring (TDM) may be of help in optimising azathioprine treatment, but data on TDM in established azathioprine therapy are lacking. We therefore measured metabolite levels in a small cohort of patients established on azathioprine therapy. PATIENTS AND METHODS: 6-Thioguanine (6-TGN) and 6-methylmercaptopurine (6-MMP) levels in erythrocytes were measured in 15 IBD outpatients established on azathioprine therapy for at least 3 months at baseline and 1, 4 and 8 weeks after inclusion (mean duration of treatment 28 months; range 7-67 months). Disease activity was evaluated by the Crohn's Disease Activity Index (Crohn's disease) or Truelove-Witts (ulcerative colitis) scores. Metabolite levels were measured by modified high-performance liquid chromatography assay (HPLC). Primary outcome measures were 6-TGN and 6-MMP metabolite levels and 95% confidence intervals (CIs). SECONDARY OUTCOMES were correlations between metabolite levels, drug dose, disease activity and laboratory parameters and compliance. RESULTS: One patient had active disease during the study period. Eleven of 15 patients (73%) completed the 8-week study period. Dropout reasons were noncompliance in three patients (20%) and intolerance in one patient (7%). PRIMARY OUTCOMES: At baseline mean 6-TGN levels were 158 (95% CI 113, 203) pmol/8.10(8) RBC (red blood cells), steadily increasing over the 8-week study period, but not significantly. Two patients had zero levels. Another two had significantly increasing levels also suggesting noncompliance. Mean 6-MMP levels showed almost a similar pattern. At baseline, levels were 2213 (95% CI 722, 3704) pmol/8.10(8) RBC. SECONDARY OUTCOMES: A correlation was found between all RBC 6-MMP levels and azathioprine dose (mg/kg bodyweight) [r = 0.43, p = 0.001] and also between the 6-MMP/6-TGN ratio and azathioprine dose (mg/kg) [r = 0.36, p = 0.010). There was no correlation between RBC 6-TGN or 6-MMP levels and haematological parameters or disease activity scores. No hepatic, pancreatic or myelotoxicity occurred.Thirteen of 15 patients (87%) had baseline steady-state 6-TGN levels below the therapeutic threshold of 235 pmol/8.10(8) RBC. Forty percent (6/15) of our patients were noncompliant; TDM revealed this noncompliance in four of the six patients (27% of all patients). CONCLUSION: Our small study demonstrates that TDM may provide insight into individual pharmacokinetics. However, TDM does not seem to be useful in patients with IBD established on azathioprine therapy and without disease activity, although it may be helpful in cases of worsening IBD activity to elucidate noncompliance or inefficient treatment.

[Diagnostic image (118). A man suffering from severe abdominal pain. Chronic recurrent pancreatitis]. / Diagnose in beeld (118). Een man met hevige buikpijn. Chronische recidiverende pancreatitis.

A 50-year-old man with a history of alcohol abuse had recurring severe epigastric pain. He suffered from chronic recurrent pancreatitis; the CT-scan showed a chain-of-lakes pattern of the pancreatic duct.

Chemoprevention of colorectal cancer by non-steroidal anti-inflammatory drugs.

AIM: To critically analyse the role of NSAIDs in colorectal cancer. METHODS: Update of the chemoprotective effect of NSAIDs on colorectal cancer. RESULTS AND CONCLUSION: Over the past 20 years exciting developments in clinical and basic research have opened up the possibility of NSAID-induced colorectal cancer chemoprevention. In particular, disclosure of the multistep genetic pathway of colorectal carcinogenesis and recognition of the impact of the COX-2 gene on this process have been of utmost importance. These findings have led to the possibility of colorectal cancer prevention by the administration of agents such as NSAIDs. Although it is accepted that these agents are potent inhibitors of colorectal carcinogenesis, their side effects in long-term use are of concern to clinicians dealing with colorectal cancer prevention. Moreover, neither the dose nor the duration of the medication, nor the most ideal compound with respect to protective effects against colorectal cancer, has been defined. Recently, selective COX-2 inhibitors have been developed which may show additional benefit compared to the classical NSAIDs. However, their efficacy and safety profiles need to be established firmly before large-scale use in colorectal cancer prevention can be considered. Based on the exciting developments it is anticipated that a more precise understanding of the molecular details of colorectal carcinogenesis will finally lead to the optimal chemopreventive regimen.

Mesalazine-induced apoptosis of colorectal cancer: on the verge of a new chemopreventive era?

BACKGROUND: It is an accepted fact that non-steroidal anti-inflammatory drugs (NSAIDs) are potent inhibitors of colorectal carcinogenesis. However, the major disadvantages of NSAIDs are gastrointestinal and renal toxicity. We conducted a prospective pilot study on the effects of the safe salicylic acid derivative, mesalazine, on apoptosis and proliferation of tumour cells and on normal tissue in colorectal cancer patients. METHODS: Patients with colorectal cancer were asked to take mesalazine enemas for 14 days. Biopsies from malignant and normal tissue were taken prior to and after this treatment. Apoptosis was scored on haematoxylin/eosin-stained tissue sections, and cell proliferation was assessed by the proliferation marker Ki-67. RESULTS: Ten out of 14 patients completed the study. The apoptotic score increased significantly in the tumour samples (pre-treatment 14.6 +/- 1.3 vs. post-treatment 19.4 +/- 0.8; P < 0.03). The apoptotic index in the normal mucosa was unchanged (pre-treatment 3.1 +/- 0.4 vs. post-treatment 2.9 +/- 0.3; N.S.). The cell proliferation in malignant tissue, according to the Ki-67 score, was hardly affected by mesalazine (pre-treatment 522 +/- 38 vs. post-treatment 493 +/- 39; N.S.). There was no effect on the Ki-67 index of normal mucosa (pre-treatment 24.2 +/- 2.0 vs. post-treatment 28.3 +/- 2.0; N.S.). CONCLUSIONS: This pilot study conducted in patients with colorectal cancer clearly shows that mesalazine selectively induces apoptosis of tumour cells. On the basis of these findings, which need to be confirmed in larger studies, it may be speculated that 5-ASA could be useful in the chemoprevention of colorectal cancer.

Treatment of mesenteric desmoid tumours with the anti-oestrogenic agent toremifene: case histories and an overview of the literature.

Desmoid tumours are histologically benign but due to their infiltration and compression of surrounding structures potentially life-threatening fibromatous lesions of unknown aetiology. The annual incidence rate is 2-4 per million people. The mesenteric variant constitutes about 10% of all desmoid tumours, although in familial adenomatous polyposis (FAP) patients this may be up to 70%. Due to the small number of patients with mesenteric desmoids the therapy is mainly empirical. This report describes the rationale as well as the value of the short- and long-term treatment (up to 6 years) with the anti-oestrogenic agent toremifene in combination with sulindac in two patients suffering from such a mesenteric desmoid tumour. These patients did not respond to sulindac alone and previous treatment with tamoxifen together with this non-steroidal anti-inflammatory drug had also failed. An overview of the literature on the management of these dismal tumours is presented.

Extracolonic manifestations of familial adenomatous polyposis: desmoid tumours, and upper gastrointestinal adenomas and carcinomas.

It is well known that patients with familial adenomatous polyposis (FAP) are at considerable risk of developing extracolonic manifestations of the disease. Particularly, desmoid tumours of the abdominal cavity, and duodenal adenomas and carcinomas are the most serious ones. It is estimated that some 10% of the FAP patients will develop desmoids, whereas 50-90% of the FAP patients will get duodenal adenomas predominantly concentrated on or around the major papilla. Desmoid tumours and duodenal carcinomas are major causes of death in those patients in whom a prophylactic (procto)colectomy has been performed. Desmoids are histologically benign tumours, composed of mature fibroblasts. They usually grow slowly but they can become quite large and may compress or infiltrate surrounding viscera, which might cause significant morbidity as well as mortality. Successful treatment of these tumours is extremely difficult as surgical therapy often requires the removal of considerable lengths of small bowel. Moreover, surgical therapy may lead to uncontrollable bleeding and is seldom radical. Chemotherapy with cytoxic agents seems promising but so far the data are too few for firm conclusions to be drawn. The same holds true for drug regimens which interfere with the metabolic and hormonal metabolism of the tumour. Although various lines of evidence suggest that the adenoma-carcinoma sequence, which is generally accepted for colorectal adenomas, also applies for the duodenal adenomas in FAP patients, it is not clear whether we should screen these patients for upper gastrointestinal adenomas or not. As these polyps are usually small, sessile, multiple and difficult to remove, the benefit of endoscopic surveillance would be the early detection of cancer rather than eradication of the polyps. In addition, evidence that screening and early treatment leads to improvement of the prognosis is not available. Although the role of (procto)colectomy in the treatment of large-bowel polyps is well established in FAP patients, the treatment of their duodenal counterparts is still open for debate. The risk of the development of periampullary cancer is not high enough to warrant an aggressive prophylactic surgical approach, i.e. a Whipple's procedure, immediately after the discovery of duodenal adenomas. The considerable morbidity and mortality rates of this procedure must be weighted against a putative benefit of screening.