Karin Dilger

Azathioprine versus mesalazine for prevention of postoperative clinical recurrence in patients with Crohn's disease with endoscopic recurrence: efficacy and safety results of a randomised, double-blind, double-dummy, multicentre trial

Objective The aim of the study was to compare azathioprine versus mesalazine tablets for the prevention of clinical recurrence in patients with postoperative Crohns disease (CD) with moderate or severe endoscopic recurrence. Methods This was a 1 year, double-blind, double-dummy, randomised study which took place in 21 gastroenterology centres in Austria, the Czech Republic, Germany and Israel. The study participants were 78 adults with CD who had undergone resection with ileocolonic anastomosis in the preceding 6–24 months without subsequent clinical recurrence and with a Crohns disease activity index (CDAI) score <200, but with moderate or severe endoscopic recurrence. The study drugs were azathioprine 2.0–2.5 mg/kg/day or mesalazine 4 g/day over 1 year. The primary end point was therapeutic failure during 1 year, defined as a CDAI score ≥200 and an increase of ≥60 points from baseline, or study drug discontinuation due to lack of efficacy or intolerable adverse drug reaction. Results Treatment failure occurred in 22.0% (9/41) of azathioprine-treated patients and 10.8% (4/37) of mesalazine-treated patients, a difference of 11.1% (95% CI −5.0% to 27.3%, p=0.19). Clinical recurrence was significantly less frequent with azathioprine versus mesalazine (0/41 (0%) vs 4/37 (10.8%), p=0.031), whereas study drug discontinuation due to adverse drug reactions only occurred in azathioprine-treated patients (9/41 (22.0%) vs 0%, p=0.002). The proportion of patients showing ≥1 point reduction in Rutgeerts score between baseline and month 12 was 63.3% (19/30) and 34.4% (11/32) in the azathioprine and mesalazine groups, respectively (p=0.023). Conclusions In this population of patients with postoperative CD at high risk of clinical recurrence, superiority for azathioprine versus mesalazine could not be demonstrated for therapeutic failure. Clinical trial registration number NCT00946946.

Influence of age and cytochrome P450 2C9 genotype on the steady-state disposition of diclofenac and celecoxib

ObjectiveTo analyse the influence of age and cytochrome P450 (CYP) 2C9 genotype on the steady-state disposition of the standard NSAID diclofenac and the new COX-2 selective inhibitor celecoxib, both of which are metabolised by the polymorphically expressed CYP2C9.DesignDouble-blind randomised crossover study under steady-state conditions.Subjects12 young (age 32 ± 5 years, bodyweight 71 ± 12kg; mean ± SD) and 12 elderly (68 ± 2 years, 82 ± 15kg) healthy, drug-free, nonsmoking Caucasians of both sexes.MethodsAll subjects received oral celecoxib (200mg twice daily) and diclofenac (75mg twice daily) for 15 days separated by a drug-free interval of at least 3 weeks. Following the last morning dose, multiple blood samples were taken for 25 hours. Concentrations of celecoxib and diclofenac were measured by specific and sensitive high performance liquid chromatography. Identification of CYP2C9 genotype was performed by genomic DNA sequencing. Pharmacokinetic parameters for total and unbound drugs were individually analysed by noncompartmental techniques.ResultsFor diclofenac, area under the concentration-time curve over the dosage interval (AUC τ) was larger in young subjects (3.2 ± 1.0 mg · h/L) than in older individuals (2.4 ± 0.4 mg · h/L; p < 0.05). As the terminal half-life (t½z) was very similar in both groups (3.9 ± 4.4 vs 3.5 ± 3.3 hours), either less complete absorption in the elderly or their higher bodyweight could account for the difference. For celecoxib, AUCτ (5.8 ± 1.7 vs 5.6 ± 2.3 mg · h/L) and t½z (11.8 ± 8.7 vs 11.2 ± 2.9 hours) were almost identical in young and older subjects. Plasma protein binding of both NSAIDs was unaffected by age, and apparent oral clearances for unbound drugs were not different between the two groups of healthy subjects. When considering the genotype of all individuals (CYP2C9*1/*1, n = 10; CYP2C9*1/*2, n = 6; CYP2C9*2/*2, n = 2; CYP2C9*1/*3, n = 4; CYP2C9*3/*3, n = 1), no association with any pharmacokinetic parameter of either drug was apparent. Moreover, there was no significant correlation between the AUC values of celecoxib and diclofenac.ConclusionsAge and CYP2C9 genotype do not significantly affect the steady-state disposition of celecoxib and diclofenac. This would indicate that both drugs need no dosage reduction in the elderly (at least up to 75 years) and that, besides CYP2C9, additional CYP species contribute to the elimination of both agents.

Pharmacokinetics and the pharmacodynamic action of midazolam in young and elderly patients undergoing tooth extraction

To determine whether age‐dependent pharmacokinetic and pharmacodynamic alterations account for a more pronounced response to benzodiazepines among elderly patients.

Identification of Budesonide and Prednisone as Substrates of the Intestinal Drug Efflux Pump P-glycoprotein

Steroid resistance is a major problem in the management of patients with inflammatory bowel disease. In Crohn disease, poor response to corticosteroids has been related to increased expression of the drug efflux pump, P-glycoprotein. However, it has not been investigated thoroughly whether corticosteroids commonly used for drug therapy in inflammatory bowel disease are substrates of P-glycoprotein. We tested the hypothesis that budesonide and prednisone are substrates of P-glycoprotein thereby possibly contributing to variable therapeutic effects. Polarized, basal to apical transport of [3H]budesonide and [3H]prednisone was studied in monolayers of L-MDR1 cells (LLC-PK1 cells stably transfected with human MDR1 cDNA) and Caco-2 cells, both of which express P-glycoprotein in their apical membrane. Drug transport was measured during 4 hours at substrate concentrations of 5 μM. Net transport rates and permeability coefficients were calculated. Inhibition of P-glycoprotein–mediated transport across Caco-2 monolayers was determined after addition of the P-glycoprotein inhibitor PSC-833. The net transport rate from the basolateral to the apical side was significantly higher in L-MDR1 than in LLC-PK1 cells for both budesonide and prednisone. Apparent permeability coefficients of budesonide and prednisone reflected polarized transport from basal to apical. PSC-833 inhibited the polarized transport of both corticosteroids. In conclusion, budesonide and prednisone were identified as substrates of the intestinal drug efflux pump, P-glycoprotein. Therefore, drug secretion via P-glyco-protein into gut lumen might play a more important role in pharmacokinetics and pharmacodynamics of these corticosteroids than currently appreciated in gastroenterological practice.

Consequences of rifampicin treatment on propafenone disposition in extensive and poor metabolizers of CYP2D6

Propafenone undergoes extensive metabolism both by phase I and phase II enzymes: cytochrome P4502D6 (CYP2D6) dependent polymorphic hydroxylation to its main metabolite 5-OH-propafenone, CYP3A4/1A2 dependent N-dealkylation and further glucuronidation and sulfation. Since CYP2D6 is not inducible by rifampicin, an important drug interaction between rifampicin and propafenone is not to be expected a priori. However, non-CYP2D6-dependent pathways may be induced as a case report described dramatically lowered plasma concentrations of propafenone with loss of dysrhythmia control associated with rifampicin treatment. Therefore, this study aimed to investigate induction properties of rifampicin on propafenone disposition in extensive metabolizers and poor metabolizers of CYP2D6. Six extensive metabolizers and six poor metabolizers ingested 600 mg rifampicin once daily for nine consecutive days. The day before the first rifampicin dose and on the day of the last rifampicin dose each individual received a single intravenous (i.v.) infusion of 140 mg unlabelled propafenone and 2 h later a single dose of 300 mg deuterated propafenone orally (p.o.). During enzyme induction maximum QRS prolongation decreased significantly after propafenone p.o. (21 +/- 7% versus 13 +/- 6% in extensive metabolizers, P < 0.01; 15 +/- 6% versus 9 +/- 6% in poor metabolizers, P < 0.01) and not after propafenone i.v. In parallel, there were no substantial differences in pharmacokinetics of propafenone i.v. by rifampicin. However, bioavailability of propafenone dropped from 30 +/- 15% to 10 +/- 8% in extensive metabolizers (P < 0.01) and from 81 +/- 6% to 48 +/- 8% in poor metabolizers (P < 0.001). Following propafenone p.o. clearances through N-dealkylation (4.1 +/- 2.1 ml/min versus 23.5 +/- 12.6 ml/min in extensive metabolizers, P < 0.01; 3.4 +/- 1.3 ml/min versus 16.0 +/- 5.5 ml/min in poor metabolizers, P < 0.001) and glucuronidation (123 +/- 48 ml/min versus 457 +/- 267 ml/min in extensive metabolizers, P < 0.05; 43 +/- 9 ml/min versus 112 +/- 34 ml/min in poor metabolizers, P < 0.01), but not 5-hydroxylation increased regardless of phenotype indicating substantial enzyme induction. Clearances to propafenone sulfate and conjugates of 5-OH-propafenone were significantly enhanced by rifampicin treatment in poor metabolizers (P < 0.01). Thus, induction of both phase I pathways (CYP3A4/1A2) and phase II pathways (glucuronidation, sulfation) of propafenone by rifampicin resulted in a clinically relevant metabolic drug interaction which was more pronounced in extensive metabolizers than in poor metabolizers with regard to percentage decrease in bioavailability of propafenone.

Enzyme induction in the elderly: Effect of rifampin on the pharmacokinetics and pharmacodynamics of propafenone

A clinical study on enzyme induction in elderly subjects was performed by investigation of the effect of rifampin (INN, rifampicin) on propafenone disposition. Propafenone was chosen as a model drug because of its complex metabolism that permits the simultaneous in vivo assessment of induction of phase 1 and phase 2 pathways.

Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health

BACKGROUND & AIMS Ursodeoxycholic acid (UDCA) exerts anticholestatic, antifibrotic and antiproliferative effects in primary biliary cirrhosis (PBC) via mechanisms not yet fully understood. Its adequate biliary enrichment is considered mandatory for therapeutic efficacy. However, precise determination of biliary enrichment of UDCA is not possible in clinical practice. Therefore, we investigated (i) the relationship between biliary enrichment and plasma pharmacokinetics of UDCA, (ii) the effect of UDCA on plasma and biliary bile acid composition and conjugation patterns, and (iii) on the intestinal detoxification machinery in patients with PBC and healthy controls. METHODS In 11 PBC patients and 11 matched healthy subjects, cystic bile and duodenal tissue were collected before and after 3 weeks of administration of UDCA (15 mg/kg/day). Extensive pharmacokinetic profiling of bile acids was performed. The effect of UDCA on the intestinal detoxification machinery was studied by quantitative PCR and Western blotting. RESULTS The relative fraction of UDCA and its conjugates in plasma at trough level[x] correlated with their biliary enrichment[y] (r=0.73, p=0.0001, y=3.65+0.49x). Taurine conjugates of the major hydrophobic bile acid, chenodeoxycholic acid, were more prominent in bile of PBC patients than in that of healthy controls. Biliary bile acid conjugation patterns normalized after treatment with UDCA. UDCA induced duodenal expression of key export pumps, BCRP and P-glycoprotein. CONCLUSIONS Biliary and trough plasma enrichment of UDCA are closely correlated in PBC and health. Taurine conjugation may represent an adaptive mechanism in PBC against chenodeoxycholic acid-mediated bile duct damage. UDCA may stabilize small intestinal detoxification by upregulation of efflux pumps.

Effects of celecoxib and diclofenac on blood pressure, renal function, and vasoactive prostanoids in young and elderly subjects

Cyclooxygenase (COX) inhibitors are among the most widely used drugs, especially in the elderly. It has been claimed that the new COX‐2 inhibitors offer advantages in terms of drug safety. To test this hypothesis, the authors compared in a double‐blind, randomized trial the effects of celecoxib (200 mg bid) and diclofenac (75 mg bid) on blood pressure and renal function in two groups (each n =12) of young (mean age = 32 years) and elderly (mean age = 68 years) normotensive subjects. Changes from baseline in the 24‐hour blood pressure profiles, parameters of the renin‐angiotensin‐aldosterone system, inulin clearance, urinary marker proteins, and eicosanoid excretion were monitored during the treatment period of 2 weeks. Comparison between celecoxib and diclofenac showed no significant difference in minor alterations of blood pressure. During daytime, there was a trend to elevation of mean arterial blood pressure (mmHg) by celecoxib in the elderly of 2.8 (95% confidence interval [Cl] = −2.5 to 8.2) in comparison with the young subjects of −1.3 (95% Cl = −3.7 to 1.0); there was also a trend to elevation of mean arterial blood pressure by diclofenac in the elderly of 4.1 (95% Cl = −1.2 to 9.4) in comparison with the young subjects of 0.4 (95% Cl =−2.4 to 3.2). In both populations, the authors found no significant drug effects on the parameters of the renin‐angiotensin‐aldosterone system, inulin clearance, and urinaiy marker proteins. As expected, diclofenac reduced excretion of all prostanoids, whereas celecoxib did not affect production of TxB2 and its metabolites. Neither in young nor in elderly normotensive subjects were blood pressure and renal function significantly affected by a short‐terrn treatment with standard doses of celecoxib and diclofenac. Therefore, normal aging appears not to represent a special risk factor in therapy with these two agents.

Adverse events in clinical trials with azathioprine and mesalamine for prevention of postoperative recurrence of Crohn's disease

A 36 year old female patient was reviewed at the gastrointestinal clinic. She had, since the age of 15 years, been affected by troublesome orofacial granulomatosis (OFG) manifest as lower lip swelling together with a midline fissure. In the past she had received numerous therapies, including intralesional and systemic corticosteroid (short term benefit only), cinnamon and a benzoate free diet (lack of compliance), azathioprine (intolerance), and topical tacrolimus (ineffective). In 2001, due to increasing distress about her appearance compounded by her forthcoming wedding, we decided to treat her with an infliximab infusion at 5 mg/kg. Within seven days there was a noticeable improvement, followed by complete healing of her labial fissure six weeks later, just prior to her wedding. Two weeks after this she found out she was pregnant. She subsequently gave birth to a healthy baby boy …

CYP2E1 activity in patients with alcoholic liver disease

BACKGROUND/AIMS In addition to the possible toxicological impact of cytochrome P4502E1 (CYP2E1) in alcohol-induced liver damage, its activity can be regarded as a variable for drug action in patients with alcoholic liver disease as CYP2E1 is involved in the metabolism of several drugs, for example, paracetamol and halogenated anesthetics. The purpose of our study was to acquire detailed knowledge of CYP2E1 activity in patients with progressingly severe manifestations of alcoholic liver disease. METHODS The concentration ratio of 6-hydroxy-chlorzoxazone/chlorzoxazone in plasma 2 h after ingestion of 500 mg chlorzoxazone (so-called metabolic ratio) has been shown to reflect CYP2E1 activity in vivo. We examined CYP2E1 activity in 56 Caucasian inpatients with minor (n=20), more pronounced (n=14) and severe alcoholic liver disease (n=22). Alcohol abusers were compared to healthy teetotallers (n=14). RESULTS Metabolic ratios were increased 3-fold in actively drinking (ethanol-induced) compared to abstaining (non-induced) patients with alcoholic liver disease (1.19+/-0.84 vs. 0.44+/-0.45, mean+/-SD, (p<0.0001). CYP2E1 activity was significantly lower in non-induced patients with severe alcoholic liver disease (0.19+/-0.10) than in healthy controls (0.50+/-0.28, p<0.01), abstaining alcohol abusers with minor (0.67+/-0.60, p<0.01) and more pronounced alcoholic liver disease (0.53+/-0.31, p<0.01). When non-induced patients with alcoholic liver disease were arranged in progressing order of liver damage (minor, more pronounced, severe alcoholic liver disease), there was a significant decline in CYP2E1 activity (p=0.0008). CONCLUSIONS In non-induced patients, CYP2E1 activity decreases in line with severity of alcoholic liver disease. CYP2E1-mediated drug metabolism is significantly impaired in severe alcoholic liver disease.