Percutaneous endoscopic colostomy for adults with chronic constipation: Retrospective case series of 12 patients.

BACKGROUND: Percutaneous endoscopic colostomy (PEC) is a technique derived from percutaneous endoscopic gastrostomy. When conservative treatment of chronic obstipation fails, colon irrigation via PEC seems less invasive than surgical interventions. However, previous studies have noted high complication rates of PEC, mostly related to infections. Our aim was to report our experiences with PEC in patients with chronic refractory constipation. METHODS: Retrospective analysis of all patients who underwent PEC for refractory constipation in our secondary referral hospital between 2009 and 2016. KEY RESULTS: Twelve patients received a PEC for chronic, refractory constipation. Short-term efficacy for relief of constipation symptoms was good in 8 patients and moderate in 4 patients. Two patients had the PEC removed because of spontaneous improvement of constipation. Three patients, who initially noticed a positive effect, preferred an ileostomy over PEC after 1-5 years. One PEC was removed because of an abscess. Long-term efficacy is 50%: 6 patients still use their PEC after 3.3 years of follow-up. No mortality occurred. CONCLUSIONS AND INTERFERENCES: PEC offers a technically easily feasible and safe treatment option for patients with chronic constipation not responding to conventional therapy. Long-term efficacy of PEC in our patients is 50%.

Safety and efficacy of a fully covered large-diameter self-expanding metal stent for the treatment of upper gastrointestinal perforations, anastomotic leaks, and fistula.

Upper gastrointestinal perforations, fistula, and anastomotic leaks are severe conditions with high mortality. Temporary endoscopic placement of fully covered self-expanding metal stent (fSEMS) has emerged as treatment option. Stent migration is a major drawback of currently used stents. Migration is often attributed to a relatively too small stent diameter as esophageal stents were initially intended for the treatment of strictures. This study aimed to investigate the safety and efficacy of a large-diameter fSEMS for treatment of these conditions. Data were retrospectively collected from patients who received this stent in the Netherlands between March 2011 and August 2013. Clinical success was defined as sufficient leak closure after stent removal as confirmed by endoscopy or X-ray with oral contrast without surgical intervention or placement of another type of stent. Adverse events were graded according a standardized grading system. Stent placement was performed in 34 patients for the following indications: perforation (n = 6), anastomotic leak (n = 26), and fistula (n = 2). Technical success rate was 97% (33/34). Clinical success rate was 44% (15/34) after one stent and 50% (17/34) after an additional stent. There were no severe adverse events and stent-related mortality. The overall adverse event rate was 50% (all graded 'moderate'). There were 14 (41%) stent migrations (complete n = 8, partial n = 6). Other adverse events were bleeding (n = 2) and aspiration pneumonia (n = 1). Reinterventions for failure of the large-diameter fSEMS were placement of another type of fSEMS (n = 4), surgical repair (n = 3), or esophagectomy (n = 1). Eleven patients (32%) died in-hospital because of persisting intrathoracic sepsis (n = 10) or preexistent bowel ischemia (n = 1). This study suggests that temporary placement of a large-diameter fSEMS for the treatment of upper gastrointestinal perforations, fistula, and anastomotic leaks is safe in terms of severe adverse events and stent-related mortality. The larger diameter does not seem to prevent stent migration.

The pharmacokinetic effect of adalimumab on thiopurine metabolism in Crohn's disease patients.

BACKGROUND AND AIMS: A drug interaction between infliximab and azathioprine has previously been reported in Crohn's disease patients: the concentration of the main active thiopurine metabolites, the 6-thioguanine nucleotides (6-TGN), increased 1-3 weeks after the first infliximab infusion by 50% compared to baseline. The aim of this prospective study was to determine the effect of adalimumab on thiopurine metabolism in Crohn's disease patients, evaluated by 6-TGN and 6-methylmercaptopurine ribonucleotides (6-MMPR) concentration measurement. METHODS: Crohn's disease patients on azathioprine or mercaptopurine maintenance therapy starting with concomitant adalimumab treatment were included. 6-TGN and 6-MMPR concentrations were determined before initiation of adalimumab and after 2, 4, 6 and 12 weeks of combination therapy. The activity of three essential enzymes involving thiopurine metabolism, thiopurine S-methyltransferase (TPMT), hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and inosine-triphosphate pyrophosphatase (ITPase), was evaluated at baseline and week 4. Clinical outcome was evaluated by the Crohn's disease activity index and C-reactive protein concentrations at baseline, week 4 and week 12. RESULTS: Twelve Crohn's disease patients were analyzed. During the follow-up period of 12 weeks the median 6-TGN and 6-MMPR concentrations did not significantly change compared to baseline. TPMT, ITPase and HGPRT enzyme activity did not change either after 4 weeks. In two patients (17%) myelotoxicity was observed within 2-4 weeks, in whom both low therapeutic 6-TGN and 6-MMPR concentrations were found. CONCLUSIONS: In this study in Crohn's disease patients no pharmacokinetic interaction was shown between adalimumab and the conventional thiopurines, azathioprine and mercaptopurine.

Safe 6-thioguanine therapy of a TPMT deficient Crohn's disease patient by using therapeutic drug monitoring.

The immunosuppressive thiopurines, azathioprine (AZA) and 6-mercaptopurine (6-MP), have proven efficacy in steroid-dependant or refractory inflammatory bowel disease (IBD). In case of TPMT deficiency serious myelosuppression may occur. 6-thioguanine (6-TG), has been suggested in case of AZA and 6-MP resistant or intolerant patients. Our case demonstrates that very low dose 6-TG under close clinical surveillance and frequent therapeutic drug monitoring, may be a rescue drug for IBD-patients with low or without functional TPMT activity.

Absence of nodular regenerative hyperplasia after low-dose 6-thioguanine maintenance therapy in inflammatory bowel disease patients.

BACKGROUND: The use of 6-thioguanine has been proposed as a rescue drug for inflammatory bowel disease patients. Initial data on short-term efficacy and toxicity of 6-thioguanine were promising; however, these have been challenged by reports concerning its potential hepatotoxic effect (nodular regenerative hyperplasia). We proposed that these histological liver abnormalities may well be dose- or level-dependent. AIMS: We performed a prospective multi-centre study on the hepatotoxic potential of long-term and (as compared with prior studies) low-dose 6-thioguanine use. PATIENTS: Inflammatory bowel disease patients using 6-thioguanine for at least 30 consecutive months and consenting to undergo a liver biopsy were enrolled. METHODS: Liver biopsy specimens were scored by two pathologists, unaware of clinical data. Laboratory parameters, determined prior to initiation of 6-thioguanine therapy and prior to biopsy, were reviewed. RESULTS: Twenty-eight biopsies were analysed. The majority of patients (89%) were azathioprine and/or 6-mercaptopurine intolerant inflammatory bowel disease patients. In 26 patients (93%) no signs of nodular regenerative hyperplasia were detected; in two additional patients nodular regenerative hyperplasia could not be excluded due to inconclusive pathological findings. The mean 6-thioguanine dosage, 6-thioguaninenucleotides level, duration of use and cumulative dosage were 19.5mg, 564 pmol/8 x 10(8) RBC, 38 months and 22491 mg, respectively. CONCLUSIONS: We have demonstrated that low-dose 6-thioguanine maintenance therapy in inflammatory bowel disease patients is not likely to be associated with induction of nodular regenerative hyperplasia. The induction of nodular regenerative hyperplasia appears to be 6-thioguanine dose or 6-thioguaninenucleotides level dependent.

Pancytopenia due to high 6-methylmercaptopurine levels in a 6-mercaptopurine treated patient with Crohn's disease.

In a 23-year-old female with colonic Crohn's disease 6-mercaptopurine 100 mg daily (1.7 mg/kg) was added to mesalamine and prednisolone therapy because of ongoing disease activity. One month later she had fever and a pancytopenia. 6-methylmercaptopurine ribonucleotides levels were extremely elevated (57,000 pmol/8x10(8) red blood cells) and 6-thioguanine nucleotides levels were subtherapeutically (126 pmol/8x10(8) red blood cells). Genotyping showed a wildtype thiopurine S-methyltransferase TPMT(H/H) (*1/*1) genotype and a wildtype inosine triphosphate pyrophosphatase gene. TPMT and inosine triphosphate pyrophosphatase activity were normal. The pancytopenia recovered spontaneously within a few weeks, parallel with decreasing 6-methylmercaptopurine ribonucleotides levels after interrupting 6-mercaptopurine treatment. Epstein-Barrvirus, Cytomegalovirus and Herpesvirus infections were excluded by serology. This is the first report of pancytopenia due to extremely high 6-methylmercaptopurine ribonucleotides levels. No relation was found with the genotype of TPMT and inosine triphosphate pyrophosphatase enzymes, which play key roles in the thiopurine metabolic pathway. Apparently, 6-methylmercaptopurine ribonucleotides metabolites can cause pancytopenia, as was already known for 6-thioguanine nucleotides.

Toxicity of 6-thioguanine: no hepatotoxicity in a series of IBD patients treated with long-term, low dose 6-thioguanine. Some evidence for dose or metabolite level dependent effects?

BACKGROUND: 6-Thioguanine is used in inflammatory bowel disease since 2001, with promising short-term results. In 2003, liver histology of some 6-thioguanine treated patients showed nodular regenerative hyperplasia. Recently, magnetic resonance imaging revealed nodular regenerative hyperplasia in patients with normal histology. AIMS: Investigating the presence of nodular regenerative hyperplasia in long-term 6-thioguanine treated patients. PATIENTS AND METHODS: Inflammatory bowel disease patients, using 6-thioguanine minimally 24 months, were asked to undergo liver biopsy and magnetic resonance imaging. RESULTS: Fourteen patients used 6-thioguanine minimally 24 months, 13 participated. Mean 6-thioguanine therapy duration, daily dose and 6-thioguanine nucleotide levels were: 36 months, 18.8 mg (0.28 mg/kg) and 705 pmol/8x10(8) erythrocytes, respectively. Liver histology and magnetic resonance imaging showed no nodular regenerative hyperplasia. DISCUSSION: Liver biopsy and magnetic resonance imaging showed no nodular regenerative hyperplasia in these long-term 6-thioguanine treated inflammatory bowel disease patients. 6-thioguanine dose and metabolite levels were lower compared with previous nodular regenerative hyperplasia reports, suggesting dose or metabolite level-dependent effects. Otherwise, nodular regenerative hyperplasia is related with inflammatory bowel disease itself and immunosuppressives, including azathioprine and 6-mercaptopurine. CONCLUSION: 6-Thioguanine is debated due to nodular regenerative hyperplasia. We found no nodular regenerative hyperplasia in inflammatory bowel disease patients with long-term, low dosed 6-thioguanine, suggesting metabolite level-dependent effects. Therefore, 6-thioguanine still seems useful, but in selected patients, intolerant for other immunosuppressives, low dosed and under close surveillance of metabolite levels and hepatotoxity.

Review article: thiopurines in inflammatory bowel disease.

BACKGROUND: In the past 10-20 years, knowledge of both thiopurine pharmacology and -pharmacogenetics has been extended dramatically and used to develop new strategies to improve efficacy and reduce toxicity. AIM: To review thiopurine efficacy, toxicity, pharmacology, pharmacogenetics, interactions in patients with inflammatory bowel disease. Special attention was paid to new strategies for optimization of pharmacotherapy. METHODS: To collect relevant scientific articles, a Pubmed search was performed from 1966 through January 2006 with the following key words (MeSH terms preferentially) in multiple combinations: 'azathioprine', '6-mercaptopurine', '6-MP', '6-thioguanine', '6-TG', 'thiopurine(s)', 'metabolites', 'level(s)', 'TDM', 'TMPT', 'ITPA', 'genotype(s)', 'phenotype(s)', 'inflammatory bowel disease', 'Crohn('s) disease', 'ulcerative colitis'. RESULTS: Strategies for optimization of pharmacotherapy include therapeutic drug monitoring of thiopurine metabolites, geno- or phenotyping crucial enzymes in thiopurine metabolism like thiopurine S-methyltransferase and inosine triphosphate pyrophosphatase, and the use of thioguanine as such. CONCLUSIONS: Thiopurine S-methyltransferase genotyping and therapeutic drug monitoring are useful instruments for individualizing thiopurine pharmacotherapy of inflammatory bowel disease. Inosine triphosphate pyrophosphatase genotyping may be helpful in case of unexplainable myelotoxicity. In case of azathioprine- or mercaptopurine-intolerance, thioguanine seems a promising alternative. However, more knowledge needs to be gathered about its potential hepatotoxicity.

The pharmacokinetic effect of discontinuation of mesalazine on mercaptopurine metabolite levels in inflammatory bowel disease patients.

BACKGROUND: In vitro studies suggest interactions between mesalazine (mesalamine) and thiopurines by thiopurine S-methyltransferase (TPMT) inhibition, influencing the balance of hepatotoxic 6-methylmercaptopurine ribonucleotide and immunosuppressive tioguanine (thioguanine) metabolites. AIM: To examine the in vivo pharmacokinetic interaction between mesalazine and mercaptopurine. METHODS: A prospective study was performed in quiescent inflammatory bowel disease patients using the combination of mercaptopurine and mesalazine. Laboratory parameters, 6-methylmercaptopurine ribonucleotide and tioguanine levels and thiopurine S-methyltransferase activity in erythrocytes were measured at stable medication, after mesalazine discontinuation and mesalazine reintroduction, further mercaptopurine was continued. RESULTS: Seventeen patients were participated. Mean mercaptopurine dose was 0.78 mg/kg/day and median of mesalazine dose was 3000 mg/day. After mesalazine discontinuation, mean tioguanine levels changed significantly from 262 to 209 pmol/8 x 10(8) red blood cell, increasing to 270 after reintroduction. Mean 6-methylmercaptopurine ribonucleotide levels were 1422, 2149 and 1503 pmol/8 x 10(8) red blood cell respectively. Mean 6-methylmercaptopurine ribonucleotide/tioguanine ratio increased significantly from 6.3 at baseline to 11.2. Mean baseline thiopurine S-methyltransferase activity was 0.58 pmol/10(6) red blood cell/h and stable. All patients had wild-type thiopurine S-methyltransferase genotypes however, leucocyte counts were stable. DISCUSSION: A significantly higher tioguanine levels and improving 6-methylmercaptopurine ribonucleotide/tioguanine ratio were found during mesalazine/mercaptopurine combination. Theoretically, mesalazine inhibits thiopurine S-methyltransferase activity. In vivo thiopurine S-methyltransferase activity did not change, however. CONCLUSION: Mesalazine has synergistic effects on mercaptopurine therapy, but the mechanism is unclear. Combining these drugs may be further indication for mesalazine in inflammatory bowel disease treatment.

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.