Common misconceptions about 5-aminosalicylates and thiopurines in inflammatory bowel disease

Misconceptions are common in the care of patients with inflammatory bowel disease(IBD).In this paper,we state the most commonly found misconceptions in clinical practice and deal with the use of 5-aminosalicylates and thiopurines,to review the related scientificevidence,and make appropriate recommendations.Prevention of errors needs knowledge to avoid making such errors through ignorance.However,the amount of knowledge is increasing so quickly that one new danger is an overabundance of information.IBD is a ...     

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

Background and aimsA 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.MethodsCrohn'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.ResultsTwelve 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.ConclusionsIn this study in Crohn's disease patients no pharmacokinetic interaction was shown between adalimumab and the conventional thiopurines, azathioprine and mercaptopurine.     

Prevention of colorectal cancer in inflammatory bowel disease: value of screening and 5-aminosalicylates

Colorectal cancer is a serious complication of inflammatory bowel disease. Given this fact, it is necessary to examine the opportunities for current and future approaches to colorectal cancer prevention. The value of surveillance colonoscopy and chemoprevention of colorectal cancer with 5'-aminosalicylic acid has been evaluated in the recent literature. The current state of knowledge in the epidemiology of and new approaches to the prevention of cancer and dysplasia in inflammatory bowel disease were reviewed. It is concluded that there is significant preclinical and clinical evidence to suggest that 5-aminosalicylate drugs reduce the risk of colorectal neoplasia. However, the minimal dosage to achieve this chemopreventive effect remains unclear. There is also indirect evidence to suggest that surveillance colonoscopy is beneficial for patients with inflammatory bowel disease, particularly in those with long-standing pancolitis or primary sclerosing cholangitis-associated inflammatory bowel disease. However, definitive proof from prospective clinical trials is not available.     

Dose-dependent metabolism of methotrexate in man and rhesus monkeys.

Humans and rhesus monkeys receiving high-dose methotrexate (MTX) (greater than 50 mg/kg) excrete significant quantities of the metabolite, 7-hydroxy-MTX. This metabolite, though 200-fold less potent than MTX as an inhibitor of mammalian dihydrofolate reductase, is of very limited aqueous solubility, and thus may contribute to the renal toxicity of the high-dose regimen. The metabolite was not observed in previous pharmacologic studies in which conventional doses of MTX were administered (less than 10 mg/kg).     

The prevention of colitis-related cancer by 5-aminosalicylates: an appealing hypothesis that remains unproven

Whether or not 5-aminosalicylates can prevent colorectal cancer among patients with colitis remains an open question. The observational studies examining this question have provided conflicting results, but none of these studies have been of sufficient quality to provide a definitive answer one way or another.     

Maternal use of 5-aminosalicylates in early pregnancy and congenital malformation risk in the offspring

Abstract

Objective. Most previous studies have failed to demonstrate any effect of maternal use of 5-aminosalicylates (5-ASA) on malformation risk, but the number of infants studied have, in most cases, been low. The objective of the study was to get data from a large study with prospectively ascertained exposure information. Material and methods. The study was based on data in the Swedish Medical Birth Register (1996–2011) where identification of maternal drug use is made from midwife interviews in early pregnancy. The presence of congenital malformations was ascertained from three national registers. Adjusted odds ratios were calculated by the Mantel-Haenszel methodology. Results. Among 1,552,109 women, 3651 with 3721 infants had reported the use of 5-ASAs in early pregnancy. The risk of a major malformation was increased (1.37, 95% confidence interval = 1.17–1.62) and still more for a cardiovascular defect (1.74, 1.37–2.22). This effect seemed to be influenced by concomitant use of systemic glucocorticosteroids or immunosuppressants but some confounding by indication may also exist. There was no marked difference between the four 5-ASA drugs studied. Conclusions. Infants born of women who use 5-ASA drugs in early pregnancy have an increased risk of a congenital malformation, notably a cardiovascular defect. This could be a drug effect or an effect of an active inflammatory bowel disease.     

Dose-dependent influence of didanosine on immune recovery in HIV-infected patients treated with tenofovir

BACKGROUND: Antiretroviral therapy (ART) containing tenofovir disoproxil fumarate (TDF) and didanosine (ddI) has been associated with poor immune recovery despite virologic success. This effect might be related to ddI toxicity since ddI exposure is substantially increased by TDF. OBJECTIVE: To analyze whether immune recovery during ART with TDF and ddI is ddI-dose dependent. DESIGN AND METHODS: A retrospective longitudinal analysis of immune recovery measured by the CD4 T-cell slope in 614 patients treated with ART containing TDF with or without ddI. Patients were stratified according to the tertiles of their weight-adjusted ddI dose: low dose (< 3.3 mg/kg), intermediate dose (3.3-4.1 mg/kg) and high dose (> 4.1 mg/kg). Cofactors modifying the degree of immune recovery after starting TDF-containing ART were identified by univariable and multivariable linear regression analyses. RESULTS: CD4 T-cell slopes were comparable between patients treated with TDF and a weight-adjusted ddI-dose of < 4.1 mg/kg per day (n = 143) versus TDF-without-ddI (n = 393). In the multivariable model the slopes differed by -13 CD4 T cells/mul per year [95% confidence interval (CI), -42 to 17; P = 0.40]. In contrast, patients treated with TDF and a higher ddI dose (> 4.1 mg/kg per day, n = 78) experienced a significantly impaired immune recovery (-47 CD4 T cells/microl per year; 95% CI, -82 to -12; P = 0.009). The virologic response was comparable between the different treatment groups. CONCLUSIONS: Immune recovery is impaired, when high doses of ddI (> 4.1 mg/kg) are given in combination with TDF. If the dose of ddI is adjusted to less than 4.1 mg/kg per day, immune recovery is similar to other TDF-containing ART regimen.     

Dose-dependent influence of acetylsalicyclic acid on platelet functions and plasmatic coagulation factors.

Lysine salt of acetylsalicylic acid (ASA) was given to ten patients by intravenous infusion. Blood samples taken at intervals during the infusion permitted the examination of the influence of the dose of ASA on platelet functions. Aggregation was significantly reduced when 50 mg ASA had entered circulation, while a diminution of PF3 and PF4 availability could only be demonstrated when the dose had reached 500 and 200 mg, respectively. In order to exclude a longer latency time for the diminution of PF3 and pf4 availability, a second series of ten patients received intravenous injections of 100 and 300 mg ASA, respectively. From these patients, blood was taken 1 h after the injection. The decrease of PF3 and PF4 availability in these cases was comparable to the results of the first group. In a third series of patients, a daily intravenous dose of 2,000 mg ASA was given. In these cases, a moderate decrease of factors II, VII, IX and X was observed. Since the appearance of a PIVKA effect could also be demonstrated, vitamin K antagonism was assumed when a high dose of AS     

Clinical and endoscopic outcomes of patients with colonic Crohn's disease treated with 5-aminosalicylates as monotherapy

BackgroundIn spite of the lack of evidence regarding the clinical benefits of oral 5-aminosalicylic acid (5-ASA) compounds in Crohn's disease (CD), these drugs are frequently used in daily clinical practice, particularly for colonic CD. Our aim is to assess the use and clinical outcomes of 5-ASA of those patients with colonic CD treated with 5-ASA as monotherapy.MethodsPatients diagnosed with isolated colonic CD and treated with 5-ASA but never exposed to immunosuppressants or biologicals were identified from the local databases of five referral centres. A retrospective review of clinical and endoscopic outcomes was performed.ResultsOut of 545 patients with isolated colonic CD, 106 (19%) were treated with oral 5-ASA in monotherapy as maintenance therapy. The median follow-up was 144 months (interquartile range [IQR], 48–234). Almost all of the patients (92%) presented an inflammatory pattern and 11% developed perianal disease. Half of the patients had already received 5-ASA at diagnosis, and the median duration of 5-ASA treatment was 107 months (IQR 22.5–187). Endoscopic remission, as defined by the absence of ulcers at the last complete colonoscopy, was observed in 65% of those patients undergoing at least one colonoscopy during follow-up. Male gender and extraintestinal manifestations were associated with a lower likelihood of achieving endoscopic remission. Nine patients required colectomy, but mostly soon after CD diagnosis.Conclusions5-ASA seems to be of benefit in the long-term in one fifth of patients with colonic CD as the only maintenance therapy and should be considered in fragile patients with Crohn's colitis.     

Dose-dependent regulation of high-density lipoprotein metabolism with rosuvastatin in the metabolic syndrome

BACKGROUND: Low plasma concentration of high-density lipoprotein (HDL) cholesterol is a risk factor for cardiovascular disease and a feature of the metabolic syndrome. Rosuvastatin has been shown to increase HDL cholesterol concentration, but the mechanisms remain unclear. METHODS AND RESULTS: Twelve men with the metabolic syndrome were studied in a randomized, double-blind, crossover trial of 5-wk therapeutic periods with placebo, 10 mg/d rosuvastatin, or 40 mg/d rosuvastatin, with 2-wk placebo washout between each period. Compared with placebo, there was a significant dose-dependent increase in HDL cholesterol, HDL particle size, and concentration of HDL particles that contain apolipoprotein A-I (LpA-I). The increase in LpA-I concentration was associated with significant dose-dependent reductions in triglyceride concentration and LpA-I fractional catabolic rate, with no changes in LpA-I production rate. There was a significant dose-dependent reduction in the fractional catabolic rate of HDL particles containing both apolipoprotein A-I and A-II (LpA-I:A-II), with concomitant reduction in LpA-I:A-II production rate, and hence no change in LpA-I:A-II concentration. CONCLUSIONS: Rosuvastatin dose-dependently increased plasma HDL cholesterol and LpA-I concentrations in the metabolic syndrome. This could relate to reduction in plasma triglycerides with remodeling of HDL particles and reduction in LpA-I fractional catabolism. The findings contribute to understanding mechanisms for the HDL-raising effect of rosuvastatin in the metabolic syndrome with implications for reduction in cardiovascular disease.     

Therapeutic drug monitoring of thiopurine metabolites in adult thiopurine tolerant IBD patients on maintenance therapy

Background and aimsTherapeutic drug monitoring of active metabolites of thiopurines, azathioprine and 6-mercaptopurine, is relatively new. The proposed therapeutic threshold level of the active 6-thioguanine nucleotides (6-TGN) is ≥ 235 pmol/8 × 10⁸ erythrocytes. The aim of this prospective cross-sectional study was to compare 6-TGN levels in adult thiopurine tolerant IBD patients with an exacerbation with those in remission, and to determine the therapeutic 6-TGN cut-off level.MethodsHundred IBD patients were included. Outcome measures were thiopurine metabolite levels, calculated therapeutic 6-TGN cut-off level, CDAI/CAI scores, thiopurine dose and TPMT enzyme activity.ResultsForty-one patients had an exacerbation, 59 patients were in remission. In 17% of all patients 6-TGN levels were compatible with non-compliance. The median 6-TGN levels were not significantly different between the exacerbation and remission group (227 versus 263 pmol/8 × 10⁸ erythrocytes, p = 0.29). The previous reported therapeutic 6-TGN cut-off level of 235 pmol/8 × 10⁸ erythrocytes was confirmed in this study. Twenty-six of the 41 patients (63%) with active disease had 6-TGN levels below this threshold and 24 of 59 IBD patients (41%) in clinical remission (p = 0.04).ConclusionsThiopurine non-compliance occurs frequently both in active and quiescent disease. 6-TGN levels below or above the therapeutic threshold are associated with a significant higher chance of IBD exacerbation and remission, respectively. These data support the role of therapeutic drug monitoring in thiopurine maintenance therapy in IBD to reveal non-compliance or underdosing, and can be used as a practical tool to optimize thiopurine therapy, especially in case of thiopurine non-response