Once versus divided daily dosing with delayed-release mesalazine: a study of tissue drug concentrations and standard pharmacokinetic parameters.

BACKGROUND: Delayed-release mesalazine is traditionally taken as three divided doses. However, it is well-recognized that dosing frequency has a significant impact on compliance and that once daily dosing is preferable. METHODS: We measured serum, urinary, faecal and rectal tissue concentrations of 5-aminosalicylic acid and N-acetyl 5-aminosalicylic acid in 24 healthy volunteers following dosing with delayed-release mesalazine, 1.2 g or 2.4 g daily, given as either a single daily dose at 08:00 hours or in three divided doses at 08:00, 13:00 and 18:00 hours. RESULTS: Urinary and faecal excretion and rectal tissue concentrations of 5-aminosalicylic acid and N-acetyl 5-aminosalicylic acid were similar following single or divided daily dosing, at both doses studied. Peak serum concentrations were found at 06:00-09:00 following divided dosing and at 17:00-20:00 following once daily dosing. However, peak and trough serum levels and serum area under curve values (AUC) were similar with both regimens and at both doses. CONCLUSIONS: Urinary, faecal and rectal tissue concentrations are similar following single or divided daily dosing. Minor differences in serum levels were apparent but maximum, minimum and AUC values were similar. Clinical trials should examine the efficacy and toxicity of once daily dosing in patients with ulcerative colitis.

The effect of cholecystokinin antagonism on postprandial lower oesophageal sphincter function in asymptomatic volunteers and patients with reflux disease.

BACKGROUND: Postprandial acid reflux is thought to be mediated by the increase in transient lower oesophageal sphincter relaxations (TLOSR) frequency and fall in lower oesophageal sphincter (LOS) pressure seen after ingestion of a meal. Studies in animals and healthy volunteers suggest that cholecystokinin (CCK) may play a role. AIM: To study the role of CCK in postprandial LOS function using the CCK antagonist loxiglumide. SUBJECTS: 10 asymptomatic volunteers (7 male, 20-29 years) and 9 patients with symptomatic gastro-oesophageal reflux (4 male, 33-66 years). METHODS: Oesophageal, LOS and gastric pressure and oesophageal pH readings were recorded for 1 h before and 2 h after intragastric infusion of a 200 kCal, 300 mL long chain triglyceride meal. Each subject underwent two studies and received intravenous loxiglumide or placebo infusion in randomized order. RESULTS: During placebo infusion, postprandial LOS pressure fell [volunteers: 17 (9-31) to 7 (1-19) mmHg (P < 0.01), patients: 15 (6-26) to 9 (2-21) mmHg (P=0.02)] and TLOSR frequency increased [volunteers: 0 (0-1) to 2 (0-7) per hour (P=0.01), patients: 0 (0-3) to 2 (0-10) per hour (P=0.03)]. Loxiglumide infusion attenuated the postprandial fall in LOS pressure and the postprandial increase in TLOSR frequency [volunteers: 0 (0-3) per hour (P=0.04 vs. placebo), patients: 0 (0-2) per hour (P=0.03 vs. placebo)], but it had only modest effects on postprandial acid exposure [volunteers: placebo 45 (0-1725) vs. loxiglumide 0 (0-443) seconds (N.S.), patients: placebo 60 (0-3442) seconds vs. loxiglumide 31 (0-1472) seconds (N.S.)]. CONCLUSIONS: Loxiglumide inhibits TLOSR and attenuates the fall in LOS pressure following a meal, but has only modest effects on postprandial gastro-oesophageal acid reflux.

Studies of autonomic function in patients with achalasia and nutcracker oesophagus.

BACKGROUND: Post-mortem studies in patients with achalasia reveal degenerative changes in the vagus and its dorsal motor nuclei suggesting the possibility of widespread autonomic dysfunction. AIMS: To study a broad range of autonomic function in patients with achalasia and nutcracker oesophagus and in asymptomatic volunteers. SUBJECTS: Patients with a manometric diagnosis of achalasia and nutcracker oesophagus and age- and sex-matched asymptomatic volunteers. METHODS: Subjects underwent measurement of: (1) pupil cycle time estimation; (2) heart rate response to the Valsalva manoeuvre, standing and deep breathing; (3) systolic blood pressure response to standing; (4) diastolic response to sustained handgrip; (5) spectral analysis of heart rate variability; and (6) heart rate and blood pressure during the Valsalva manoeuvre. RESULTS: No significant differences were found between patients with achalasia and asymptomatic volunteers. Patients with nutcracker oesophagus, however, had longer pupil cycle times (1.2 (0.9-1.4) s versus 0.9 (0.8-1.2) s, P= 0.02) and had attenuation of both the rise in the low frequency peak of heart rate variability and the fall in the high frequency peak on standing (rise in low frequency peak - patients 26.6 (10.4-52.3)% to 42.2 (15.5-54.0)%, P = 0.46, volunteers 16.9 (8.4-37.2)% to 47.4 (21.1-66.3)%, P = 0.03; fall in high frequency peak - patients 18.1 (0.9-43.3)% to 10.1 (0.5-26.6)%, P= 0.46, volunteers 24.8 (8.5-44.4)% to 9.3 (2.6-35.6)%, P= 0.03). The rise in blood pressure during the Valsalva manoeuvre was also attenuated in patients with nutcracker oesophagus compared with asymptomatic volunteers (6.9 (1.0-9.3) mmHg versus 12.9 (11 -23.0) mmHg, P < 0.01). CONCLUSIONS: Whereas tests of cardiovascular and pupillary autonomic function are normal in patients with achalasia, patients with nutcracker oesophagus show defects in both parasympathetic and sympathetic function.

Treatment of intertrochanteric femoral fractures with a proximal femoral nail (PFN): a short follow up.

Proximal femoral nails have been introduced relatively recently but have begun to compete the traditional DHS. The mechanical strength of the nail and less invasive procedure have made the procedure preferable. This is a short retrospective review of 26 cases operated in the last 2years. A retrospective review of 26 cases operated in the last two years which have completed at least a year of follow up with us. All have been treated using a PFN for unstable intertrochanteric fractures of femur. A radiological assessment was mase with serial X-rays. The operating time was found to be short, less blood loss was seen during surgery and few early complications were noted. All cases were relatively free from long-term complications. PFN is a suitable implant for unstable intertrochanteric femoral fractures needing open reduction internal fixation. It has low per operative and post operative morbidity.

Dose loading with delayed-release mesalazine: a study of tissue drug concentrations and standard pharmacokinetic parameters.

AIMS: Tissue concentrations of 5-aminosalicylic acid (5ASA) and its metabolites may influence the clinical course of inflammatory bowel disease. Since the factors that determine tissue drug concentrations are unknown we have studied the relationships between the oral dose of delayed-release mesalazine, rectal tissue drug concentrations and standard pharmacokinetic parameters. METHODS: Twelve healthy volunteers were studied following 7 days treatment with 1.2, 2.4 and 4.8 g of delayed-release mesalazine daily. 5-aminosalicylic acid and N-acetyl 5-aminosalicylic acid concentrations were measured in serum, urine, stool and rectal tissue biopsies. RESULTS: Serum concentrations and 24 h urinary excretion of 5ASA and N-acetyl 5ASA increased as the oral dose of mesalazine was increased from 1.2 g through 2.4 g to 4.8 g daily (serum area under curve (AUC):5ASA = 3. 9, 15.4 and 46.8 microg ml-1 h, P < 0.0001; N-acetyl 5ASA = 17.2, 30. 9 and 57.8 microg ml-1 h, P < 0.0001: urinary excretion: 5ASA = 1.8, 85.5 and 445 mg, P < 0.0001; N-acetyl 5ASA = 250, 524 and 1468 mg, P < 0.0001, respectively). Faecal 5ASA excretion increased as the oral dose increased from 1.2 g to 2.4 g but did not increase further with 4.8 g daily dosing whereas faecal N-acetyl 5ASA excretion was similar at all three doses. Rectal tissue concentrations of 5ASA increased markedly, and N-acetyl 5ASA increased modestly, as the dose of oral mesalazine increased from 1.2 g to 2.4 g daily but neither increased further with 4.8 g daily dosing. CONCLUSIONS: The relationship between the ingested dose of delayed-release mesalazine and rectal tissue drug concentrations is complex. Factors other than dose are likely to be important determinants of rectal tissue drug concentrations.

Simple method for the determination of 5-aminosalicylic and N-acetyl-5-aminosalicylic acid in rectal tissue biopsies.

We describe a sensitive high-performance liquid chromatographic method for the determination of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid in rectal tissue biopsies. Samples were derivatised using propionic anhydride and proteins were precipitated with methanol. A Supelcosil ABZ column (150x4.6 mm I.D., 5 microm silica particles) was used with a mobile phase comprising 0.1 M acetic acid, acetonitrile and triethylamine (1600:114:6, v/v/v). Fluorescence detection was employed and detection limits were 0.2 ng/mg tissue at a signal-to-noise ratio of three (measured concentration: 5-aminosalicylic acid, 0.254 (0.228-0.286) ng/mg, C.V. 10.7%; N-acetyl-5-aminosalicylic acid, 0.18 (0.154-0.198) ng/mg, C.V 9.8%). This assay was validated for use with serum, urine and faecal samples for which it proved to be both precise and accurate (C.V.<10%, measured concentration within 10%).

Mesalazine release from a pH dependent formulation: effects of omeprazole and lactulose co-administration.

AIMS: Delayed-release formulations of mesalazine often rely on the gastrointestinal luminal pH profile to deliver 5-aminosalicylic acid (5ASA) to the colon. The aim of this study was to examine the influence of luminal pH on mesalazine release. METHODS: We studied the effect of co-administration of omeprazole and lactulose on the steady-state pharmacokinetics of Eudragit S-coated mesalazine in healthy volunteers. RESULTS: No significant changes in urinary or faecal levels of 5ASA or its main metabolite, N-acetyl 5ASA, were apparent. CONCLUSIONS: This study suggests that co-administration of omeprazole and lactulose does not impair the release of delayed-release mesalazine.