Lisbet A. Christensen

pH-Profile and regional transit times of the normal gut measured by a radiotelemetry device

The pH of the gut lumen was measured in 39 healthy persons using a pH‐sensitive, radiotransmitting capsule. Thirteen persons were studied twice. The location of the capsule was determined by X‐ray. The pH rose from 6.4 in the duodenum to 7.3 in the distal part of the small intestine. In 17 persons the pH dropped by 0.1–0.8 pH units during the last hours of the small intestinal transit. The pH was 5.7 in the caecum, but rose to 6.6 in the rectum. Gastric residence time was 1.1 h, small intestinal transit was 8 h, and colonic transit time was 17.5 h (median values). The results provide a firmer basis for prediction of the level, and the rate of release of active substance from pH‐dependent sustained‐release oral preparations.

Very low intraluminal colonic pH in patients with active ulcerative colitis

Intraluminal gastrointestinal pH was measured in seven patients with active ulcerative colitis (four male, three female). A radiotelemetry capsule was used, and its location was determined by fluoroscopy. Satisfactory measurements were obtained from six, in all of whom pH levels were normal in the stomach and small intestine. Three patients also had normal pH values in the colon. However, in the remaining three patients very low pH levels (lowest values 2.3, 2.9, and 3.4) were found in the proximal parts of the colon. Five of the seven patients, including the three with low pH in the colon, underwent colectomy. The mechanism behind the low intraluminal pH in some patients with ulcerative colitis is speculative. Increased fecal concentrations of lactate occur in active disease, but some of the pH values measured in our study were below the pKa value of lactate. The study demonstrates that very low intraluminal pH levels in the colon occur in some patients with active ulcerative colitis. This might be an indicator of severe activity of the disease.

Topical and systemic availability of 5‐amino‐salicylate: comparisons of three controlled release preparations in man

The bioavailability of three pure 5‐aminosalicylic (5‐ASA) preparations (Asacol, Claversal, and Pentasa) was studied in 8 ileostomy patients and 12 normal subjects after 6 days of treatment with 2000 mg 5‐ASA. The local bioavailability, reflected by the 5‐ASA concentration was thereby measured at two clinically relevant areas of the gut: at the entrance to, and the exit from the colon. Estimates of the systemic bioavailability were obtained from the urinary excretions and the plasma values of 5‐ASA and Acetyl‐5‐ASA (Ac‐5‐ASA) during the three regimens. The three preparations studied are designed to release 5‐ASA at different levels in the intestine, but there was no significant difference in the 5‐ASA concentrations in the ileostomy effluents (Asacol 1.8 mmol/L, Claversal 3.4 mmol/L, Pentasa 2.0 mmol/L, median values). However, we found a smaller urinary excretion of 5‐ASA and Ac‐5‐ASA (5.2%vs Claversal 27.9% and Pentasa 23.0%, median values of ingested daily dose) and a lower concentration of Ac‐5‐ASA in the ileostomy effluents after Asacol treatment (0.8 mmol/L, median value) which indicates a more distal release from this preparation compared with Claversal (2.4 mmol/L, median value) and Pentasa (5.5 mmol/L, median value). In normal subjects a higher faecal water concentration of 5‐ASA was found after Asacol (9.8 mmol/L, median value) compared with Claversal (5.0 mmol/L, median value), whereas no difference between the faecal water concentrations of Ac‐5‐ASA was found (Asacol 21.5 mmol/L, Claversal 21.6 mmol/L, median values). This can be explained by a larger systemic absorption of 5‐ASA from Claversal, and accordingly Claversal treatment resulted in the largest urinary excretion of 5‐ASA and Ac‐5‐ ASA (43.7% us Asacol 35.6% and Pentasa 31.6 %, median values of ingested daily dose). The high Ac‐5‐ASA concentration in the ileostomy effluents and in the faeces after Pentasa, and the low plasma values, indicate a slow 5‐ASA release from this preparation throughout the small and large intestine. The results of the study indicate that Asacol is released in the distal part of the small intestine, that Pentasa is gradually released in the small and large intestine, and that Claversal shows an intermediate release pattern.

Availability of Mesalazine (5-Aminosalicylic Acid) from Enemas and Suppositories during Steady-State Conditions

The local and systemic bioavailability of a mesalazine enema (Pentasa, Ferring A/S, Denmark) and a mesalazine suppository (Pentasa, Ferring) was assessed during steady-state conditions. Eleven healthy subjects took 1 g of the enema or the suppository twice daily for 1 week, with a drug-free period of at least 1 week in between. At the end of each treatment period the urine and faeces were collected for 48 h, and the concentrations of mesalazine and the metabolite acetyl-mesalazine were measured. Plasma concentrations of drug and metabolite were measured hourly during a 12-h dose interval. The faecal water concentration of mesalazine was significantly higher after suppository treatment (55.7 mmol/l) compared with enema treatment (31.7 mmol/l) (p less than 0.01). The systemic absorption was low; 15% of daily mesalazine dose was recovered in urine after enema treatment and 10% after suppositores (p less than 0.01). Plasma concentrations were low, and no accumulation of either mesalazine or acetyl-mesalazine occurred. In conclusion, the enema and the suppository can be continuously administered as 1 g of mesalazine twice daily, respectively, giving high faecal water concentrations of mesalazine and a low systemic absorption.

Comparative bioavailability of 5-aminosalicylic acid from a controlled release preparation and an azo-bond preparation

Background: Knowledge of the bioavailability of 5‐aminosalicylic acid (5‐ASA, mesalazine) from the different 5‐ASA‐containing drugs is important for rational therapy of inflammatory bowel diseases.

Bioavailability of 5-aminosalicylic acid from slow release 5-aminosalicylic acid drug and sulfasalazine in normal children

The bioavailability of a controlled release 5-aminosalicylic acid preparation (Pentasa) was investigated in nine healthy children after a medication period of six days (1000 mg/day) and compared with sulfasalazine (Salazopyrin) (2000 mg/day). The local bioavailability in the distal gut lumen, reflected by the 5-aminosalicylic acid concentration in the fecal water, showed comparable values after Pentasa (4.44 mmol/liter) and Salazopyrin (6.25 mmol/liter). The concentration ofN-acetyl-5-ASA was significantly higher after Pentasa, reflecting the more proximal release of 5-aminosalicylic acid compared with Salazopyrin. No relation was found between the 5-aminosalicylic acid fecal water concentration and the 5-aminosalicylic acid dose per kilogram of body weight. The urinary excretion of 5-aminosalicylic acid andN-acetyl-5-aminosalicylic acid was higher after Pentasa than after Salazopyrin (32% vs 25%). Dose interval plasma concentration curves showed low values after both preparations. Based on the concept that the fecal water concentration is decisive for the efficacy of 5-aminosalicylic acid in distal inflammatory bowel disease, Pentasa treatment offers a relevant alternative in cases of Salazopyrin intolerance or allergy in children. The higher systemic bioavailability from Pentasa warrants monitoring of the renal function.

Effect of Olsalazine and Mesalazine on Intraluminal pH of the Duodenum and Proximal Jejunum in Healthy Humans

BACKGROUNDnTreatment of inflammatory bowel disease with olsalazine causes diarrhoea in 10% of patients. This is claimed to be caused by a drug effect on mucosal transport in the small intestine, which might be reflected in the intraluminal pH. We aimed to study the effect on jejunal pH of olsalazine (Dipentum) and an alternative preparation, slow-release mesalazine (Pentasa).nnnMETHODSnThirteen healthy volunteers, seven male and six female, participated in a randomized, crossover study. Steady-state conditions were obtained after ingestion of 2 g or 6 g mesalazine daily or 2 g olsalazine daily for 1 week. The pH of the duodenum and proximal jejunum was measured by using pH-sensitive, radiotransmitting capsules, the location of which was confirmed by fluoroscopy.nnnRESULTSnNo effect of either drug on duodenal pH was detected. Mean duodenal pH ranged from 6.18 to 6.22. The mean pH of the pre-medication proximal jejunum was 6.02. Mesalazine had no significant effect, but olsalazine significantly increased the pH of the proximal jejunum (mean pH, 6.47).nnnCONCLUSIONSnOur results indicate that the effect of olsalazine on jejunal transport of electrolytes and water, observed in experimental studies, also applies to human subjects in steady-state conditions, and adaptation does not occur within 6 days.

Campylobacter pylori in esophagus

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Concomitant Administration of Cimetidine and Pentasa

SummaryThe effect of cimetidine on gastrointestinal pH and on the bioavailability of mesalazine from Pentasa® tablets was investigated in 12 healthy volunteers. Each subject received Pentasa® 2g daily for 1 week, with and without concomitant administration of cimetidine 400mg twice daily in a randomised crossover study. The pH profile of the gastrointestinal tract was determined using a radiotransmitting, pH-sensitive capsule. The median gastric pH was increased to 3.1 when cimetidine was administered with Pentasa® compared with 1.8 when Pentasa® was taken alone. There was no significant change in the pH of the small intestine and colon during the 2 regimens. Concentrations of mesalazine and acetyl-mesalazine were determined from urine and faeces samples collected over the last 48 hours of each crossover period. Concomitant administration of cimetidine did not affect the faecal water concentration of mesalazine, nor the urinary excretion of drug.In conclusion, ingestion of cimetidine 800 mg/day does not change the gastrointestinal pH sufficiently to affect the bioavailability of mesalazine from Pentasa®. It is therefore unlikely that concomitant ingestion of cimetidine with Pentasa® will affect the therapeutic efficacy of the latter.