Effects of controlled-release on the pharmacokinetics and absorption characteristics of a compound undergoing intestinal efflux in humans

OBJECTIVE: The number of active pharmaceutical ingredients (API) undergoing inhibitable and saturable intestinal efflux is considerable. As a consequence, absorption and bioavailability may depend on the intestinal concentration profile of the drug and may vary as a function of dose and release rate of the drug from the dosage form. The impact of controlled versus immediate-release on the absorption of P-glycoprotein substrates is currently unknown. Thus, the main focus of the present study was a comparison of the pharmacokinetics of the P-gp model substrate talinolol following administration of immediate-release (IR) and controlled-release (CR) tablets to healthy human volunteers with a particular focus on the absorption characteristics of the active pharmaceutical ingredients. METHODS: Talinolol immediate-release (Cordanum), 100mg), one controlled-release (100mg) and two controlled-release tablets (200mg) were administered as single doses to fasting healthy volunteers in a crossover design with a 1 week washout period between treatments. Sufficient blood and urine samples were drawn and analysed using a specific HPLC method with UV detection to describe the resulting plasma and urinary excretion versus time profiles. RESULTS: The bioavailability of talinolol in term of AUC(0-->infinity) for IR talinolol was approximately twice as high as compared to the administration of the same dose in a controlled-release dosage form. After administration of talinolol IR tablets, the drug was rapidly absorbed and reached maximum concentrations C(max) of 204.5 ng/ml /-121.8 (means /-S.D.) 2h after dosing. The terminal half-life of the drug averaged 19.8h following IR administration in comparison to 32 h under CR dosing conditions. Following administration of the IR dosage form, significant secondary peaks were observed in one healthy subject. Secondary peaks were not clearly apparent in the CR plasma profiles. CONCLUSION: The present study demonstrates a considerable loss of bioavailability of drugs that are substrates of intestinal secretory transporters upon their administration in controlled-release dosage forms

Fragebogen zur Messung der psychosozialen Belastungen bei chronisch-entzundlichen Darmerkrankungen (FBCED): Konstruktion und Evaluation. [The Inflammatory Bowel Disease Stress Inventory (IBD-SI). A measure of psychosocial stress in patients with IBD]

The Inflammatory Bowel Disease Stress Inventory (IBD-SI) measures a broad spectrum of disease-specific every day stress factors in patients with inflammatory bowel disease (IBD). Based on a multistage factor analysis on 300 CED patients, the final form comprises 32 items assigned to 8 different domains: depressed mood, doctor-patient relationship, anxiety about loss of bowel control, occupational impairment, worries about deteriovation, stress from medical treatment, impairment of sexuality/partnership and physical complaints. In addition, a global stress score can be obtained. The reliability values of the 8 subscales with 4 items each indicate a good internal consistency (alpha = 0.76 - 0.89) and a high retest reliability (r = 0.75 - 0.92). Significant correlations with medical and psychological variables supports the external validity of this questionnaire

Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn's disease

BACKGROUND: Crohn's disease is a chronic inflammatory disease of the alimentary tract. Azathioprine is an effective agent in the management of chronic active Crohn's disease leading to long term remission of disease activity. Such treatment leads to limited efficacy or side effects in a small subset of patients. AIMS: To compare efficacy and side effects of treatment with azathioprine plus corticosteroids versus mycophenolate mofetil (MMF) plus corticosteroids in patients with chronic active Crohn's disease. METHODS: Seventy patients with chronic active Crohn's disease (Crohn's disease activity index (CDAI) greater than 150) were randomised for treatment with azathioprine/cortisone or MMF/cortisone. Corticosteroid dosage was tapered according to a standard protocol. Disease activity was monitored by clinical scores after one, two, three, and six months. RESULTS: Treatment of patients with moderately active (CDAI 150-300) Crohn's disease with MMF/cortisone led to a significant reduction in clinical activity scores comparable to treatment with azathioprine/cortisone. Treatment of patients with highly active Crohn's disease (CDAI greater than 300) with MMF/cortisone caused significant suppression of clinical activity earlier than azathioprine/cortisone treatment. Treatment with MMF/cortisone was associated with few adverse effects. CONCLUSION: Treatment of chronic active Crohn's disease with MMF plus cortisone appears to be effective and well tolerated and should be considered in patients allergic to azathioprine or in whom azathioprine has failed

Mycophenolate mofetil versus azathioprine in patients with chronic active ulcerative colitis: a 12-month pilot study

OBJECTIVE: Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) of unknown etiology frequently requiring long-term therapy for control of symptoms and prevention of relapse. Azathioprine (AZA) has been shown to be effective and safe in the treatment of chronic active UC. However, the alternatives to treatment with AZA are limited. Our aim was to compare the efficacy and safety of treatment with mycophenolate mofetil (MMF)/prednisolone versus standard immunosuppressive treatment with azathioprine (AZA)/prednisolone in patients with chronic active UC. METHODS: The study was designed as an open comparison of MMF versus AZA. Twenty-four patients with active UC (Rachmilewitz score > or =6 points) were randomly assigned to the MMF (20 mg/kg)/prednisolone or AZA (2 mg/kg)/prednisolone group. The initial prednisolone dosage was 50 mg and was tapered according to a standard protocol. Treatment was scheduled for 1 yr. RESULTS: The rates of remission were higher in the AZA/prednisolone group (n = 12) than in the MMF/prednisolone group (n = 12) throughout the study. Remission rates were 92% versus 67% after 4 wk, 92% versus 67% after 3 months, 92% versus 67% after 6 months, 83% versus 78% after 9 months, and 100% versus 88% after 1 yr. The number of patients not requiring steroids was higher in the AZA/prednisolone group than in the MMF/prednisolone group. Moreover, in the AZA/prednisolone group no severe adverse events were recorded, whereas in the MMF/prednisolone group two severe adverse events were observed: one patient discontinued MMF after 6 months because of recurrent upper airway infections, and one patient exhibited a bacterial meningitis after 9 months. CONCLUSIONS: Treatment with AZA/prednisolone appears to be more effective and safe compared to MMF/prednisolone in patients with chronic active UC. MMF might be an alternative treatment for patients with contraindications to AZA. To further evaluate the effects of MMF in active UC, a placebo-controlled double-blinded study appears warranted