A new concept in colonic drug targeting: a combined pH-responsive and bacterially-triggered drug delivery technology.

BACKGROUND: Current approaches to colonic drug delivery exploit one of two main physiological characteristics: the pH change or increase in bacterial numbers along the gastrointestinal tract. Here, we describe a new concept in targeted delivery, which combines these triggers to improve colonic delivery. AIM: To assess the in-vivo targeting performance of a novel colonic delivery coating comprising a mixture of pH-responsive enteric polymer (Eudragit S) and biodegradable polysaccharide (resistant starch) in a single layer matrix film. METHODS: Tablets (radio-labelled) were film-coated with the dual-mechanism coating and administered in a three-way crossover study to eight healthy volunteers (i) without food, (ii) with breakfast or (iii) 30 min before breakfast. The site of intestinal disintegration was assessed using gamma scintigraphy. RESULTS: The coated tablets were able to resist breakdown in the stomach and small intestine. Consistent disintegration of the dosage form was seen at the ileocaecal junction/large intestine. The site of disintegration remained unaffected by feeding. CONCLUSIONS: The dual-mechanism (pH/bacterial) coating provides colon-specificity. Each trigger mechanism has the capacity to act as a failsafe, ensuring appropriate targeting in the gastrointestinal tract. This platform technology has potential for systemic applications or the treatment of local disorders of the large intestine, such as inflammatory bowel disease.

[Fat, spices and gastro-oesophageal reflux]. / Fette, Gewürze und gastroösophagealer Reflux.

In spite of poor evidence, many patients with gastro-oesophageal reflux are advised to avoid fat and spices. We therefore measured gastro-oesophageal reflux after fatty and spicy meals. During three 24-h pH monitoring sessions, eight volunteers ate two identical, low fat and mild beef stews, or a hot and fatty Indian curry for lunch. Meals for dinner were the beef stew, the hot Indian curry or a mild curry. Day-time acid exposure was significantly longer after the hot curry (7.5 % [1.4 - 27.1]) than after the beef stews (2.3 % [0.4 - 9.8] and 2.5 % [0.7 - 15.7]). Night-time acid exposure was also significantly shorter after the beef stew (1.3 % [0 - 9]) than after the mild curry (2.9 % [0 - 19.1]) or the hot curry (4.6 % [0.2 - 22.5]). Within two hours postprandially, reflux was not different between the meals. The number of episodes, however, that occurred more than two hours after lunch was significantly lower after the beef stews (4 [2 - 14] and 4.5 [2 - 10]) than after the hot curry (9 [5 - 16]). The same phenomenon was observed after beef stew (0.5 [0 - 2]), mild curry (2 [0 - 4]) and hot curry (2 [1 - 9]) for dinner. We conclude that meals high in fat can provoke reflux, possibly through delayed gastric emptying. Additional spices, however, do not further increase reflux.

A scintigraphic investigation of the disintegration behaviour of capsules in fasting subjects: a comparison of hypromellose capsules containing carrageenan as a gelling agent and standard gelatin capsules.

Two-piece hard shell capsules made from hypromellose (or hydroxypropyl methylcellulose, HPMC) have been proposed as an alternative to conventional gelatin capsules for oral drug delivery; however, little is known about their in vivo behaviour. The aim of this study was to compare the disintegration of HPMC and gelatin capsules in fasted human subjects using the technique of gamma scintigraphy. HPMC capsules containing carrageenan as a gelling agent (QUALI-V(R), Qualicaps) and gelatin capsules (Qualicaps) of size 0 were filled with a lactose-based mixture. The capsules were separately radiolabelled with indium-111 and technetium-99m. Both capsules were administered simultaneously with 180ml water to eight healthy male subjects following an overnight fast. Each volunteer was positioned in front of the gamma camera and sequential 60s images were acquired in a continuous manner for 30min. No differences in the oesophageal transit of the two types of capsules were noted, with the capsules arriving in the stomach in a matter of seconds. All the capsules disintegrated in the stomach. The mean (+/-S.D.) disintegration time for the HPMC capsules was 9+/-2min (range 6-11min). The corresponding mean time for the gelatin capsules was 7+/-4min (range 3-13min). These disintegration times were not significantly different (P=0.108, paired t-test). In conclusion, HPMC and gelatin capsules show rapid and comparable in vivo disintegration times in the fasted state. HPMC capsules containing carrageenan as a gelling agent therefore offer a practical alternative to gelatin capsules as an oral drug delivery carrier.

Relationship between symptom response and oesophageal acid exposure after medical and surgical treatment for gastro-oesophageal reflux disease.

BACKGROUND: The relationship between symptom severity and objective evidence of gastro-oesophageal reflux disease (GORD) after medical and surgical treatment has recently been questioned. This study aimed to compare the symptomatic and physiological response (as measured by pHmetry) to the treatment of GORD by proton pump inhibitors (PPIs) and by laparoscopic antireflux surgery, and to examine the relationship between the patient's subjective and objective response to treatment of GORD. METHODS: Seventy patients underwent 24-h oesophageal pH measurement and DeMeester symptom assessment (for heartburn and regurgitation, grade 0-3) while off medical treatment, while taking PPIs and after laparoscopic fundoplication. RESULTS: The median percentage total time with oesophageal pH < 4 off treatment, during medical treatment and after fundoplication was 9.5, 4.3 and 0.5 per cent respectively. After medical treatment 30 patients became asymptomatic although 18 of these still had pathological reflux on pH testing. Of the 19 patients who remained symptomatic after surgery only two had pathological acid reflux. CONCLUSION: The symptomatic response of patients to either PPIs or antireflux surgery is a poor indicator of successful treatment in terms of reduced lower oesophageal acid exposure. A high proportion of patients whose symptoms are improved by PPIs still have pathological levels of acid reflux. Conversely, most patients who complain of reflux symptoms after antireflux surgery have no evidence of residual reflux on pHmetry.

Objective evaluation of small bowel and colonic transit time using pH telemetry in athletes with gastrointestinal symptoms.

BACKGROUND: Gastrointestinal (GI) disturbances are often reported by long distance runners and are more common in women, particularly after prolonged high intensity exercise. OBJECTIVES: To determine whether these symptoms could be associated with alterations in GI motility. METHODS: Small bowel and colonic transit were measured using pH telemetry in a group of 11 female athletes (age 22 to 53 years), six of whom experienced lower GI symptoms during exercise. Subjects participated in two experimental sessions: a control measurement, where small bowel transit was estimated during a rest period (R) of six hours; and an exercise session (E), where small bowel transit was measured during a one hour period of high intensity exercise (cross country running) at >70% VO(2)max. Colonic transit was estimated indirectly from determinations of whole gut transit time by radio-opaque marker. RESULTS: Small bowel transit time was 3.5 to 10.6 h (R) and 3.0 to 8.7 h (E) in asymptomatic athletes, versus 4.0 to 6.6 h (R) and 4.6 to 7.3 h (E) in symptomatic athletes (NS). Colonic transit time was 35.0 to 62.5 h (R) and 30.5 to 70.9 h (E) in asymptomatic athletes versus 20.4 to 42.9 h (R) and 21.5 to 67.2 h (E) in symptomatic athletes (NS). CONCLUSIONS: Small bowel and colonic transit times were similar in the two groups in the rest and exercise sessions. The diarrhoea seen in this study did not result from accelerated colonic transit. Other mechanisms must be sought.

Compliance measurement of lower esophageal sphincter and esophageal body in achalasia and gastroesophageal reflux disease.

Little is known about the effect of achalasia and gastroesophageal reflux disease (GERD) on compliance of the esophageal body and the lower esophageal sphincter (LES). Twenty-two patients with achalasia, 14 with GERD, and 14 asymptomatic volunteers were assessed. Recording apparatus consisted of a specially developed PVC bag tied to a compliance catheter, a barostat, and a polygraph. Intrabag pressures were increased incrementally while the bag volume was recorded. In each subject, pressure-volume graphs were constructed for both the esophageal body and LES and the compliance calculated. In achalasia, compliance of the esophageal body was significantly higher (P < 0.01) than in controls, whereas LES compliance was similar. Patients with GERD had a highly compliant LES in comparison to both controls and to patients with achalasia (P < 0.01 and P < 0.001, respectively); however there was no difference in their esophageal body compliance. In conclusion, foregut motility disorders can cause changes in organ compliance that are detectable using a barostat and a suitably designed compliance bag. Further measurement of compliance may provide clues to the pathogenesis of these disorders.

The effect of pH change on the gastric emptying of liquids measured by electrical impedance tomography and pH-sensitive radiotelemetry capsule.

Citrate phosphate buffer liquid adjusted to different pH values was used to investigate the gastric emptying profiles in human using simultaneous monitoring by electrical impedance tomography (EIT) and pH sensitive radiotelemetry capsule. No interference was observed between the two methods during data acquisition periods. A positive correlation between methods from the pooled data was demonstrated. Statistical moments analysis demonstrated a significant delay in the onset of gastric emptying and also the mean gastric residence time of the pH 3 buffer liquid (34.7-46.7 min) when compared with pH 7 buffer liquid (14.4-22.5 min). These data suggest that the negative feedback gastrin related response to acidity of the liquid was high. However, incorporation of an acid suppression compound (ranitidine), as part of the control study showed that the EIT imaging of this buffer could be successfully performed under normal physiological conditions. When 450 ml pH 7 buffer liquid was measured, no significant difference in gastric emptying rate was observed. This study demonstrated that, citrate phosphate buffers can be used as an alternative test liquid for EIT monitoring, and that pH has a systematic effect on gastric emptying and the lag phase.

The role of gastrointestinal endoscopy in long-distance runners with gastrointestinal symptoms.

BACKGROUND: Exercise-related gastrointestinal symptoms are not uncommon among athletes. The occurrence of gastrointestinal bleeding has been reported, especially in long-distance runners. We studied gastrointestinal mucosal damage, using gastrointestinal endoscopy, in competitive long-distance runners. Gastrointestinal blood loss and anaemia before and after running were also assessed. METHODS: Sixteen competitive long-distance runners (all men; age range 16-19 years) participated in the study. All runners completed a symptom questionnaire prior to a 20 km race. Stool occult blood and haematological studies (haemoglobin, haematocrit, serum iron, total iron-binding capacity [TIBC] and ferritin) were performed before and immediately after the race. Gastrointestinal endoscopy was performed to assess macroscopic changes. Colonoscopy was also performed on the patients who had positive stool occult blood before or after the race. RESULTS: Gastrointestinal symptoms were frequently experienced by the runners. Gastritis (n = 16), oesophagitis (n = 6) and gastric ulcer (n = 1) were found at gastroscopy. Colonoscopy was performed on four patients who had positive stool occult blood. One had multiple erosions at the splenic flexure and one had a rectal polyp. Five runners had anaemia, and all of these had at least one endoscopic lesion (three gastritis, two oesophagitis and one multiple erosion at the splenic flexure). There were significant changes in the following haematological parameters after the race: iron (decreased, P = 0.02), ferritin (decreased, P = 0.001) and TIBC (increased, P = 0.00005). CONCLUSIONS: Gastrointestinal symptoms and gastrointestinal mucosal damage are prevalent among long-distance runners. Prior to treatment, gastrointestinal endoscopy should be considered in long-distance runners with gastrointestinal symptoms and/or anaemia.

Intestinal luminal pH in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugs.

Measurements of luminal pH in the normal gastrointestinal tract have shown a progressive increase in pH from the duodenum to the terminal ileum, a decrease in the caecum, and then a slow rise along the colon to the rectum. Some data in patients with ulcerative colitis suggest a substantial reduction below normal values in the right colon, while limited results in Crohn's disease have been contradictory. Determinants of luminal pH in the colon include mucosal bicarbonate and lactate production, bacterial fermentation of carbohydrates and mucosal absorption of short chain fatty acids, and possibly intestinal transit. Alterations in these factors, as a result of mucosal disease and changes in diet, are likely to explain abnormal pH measurements in inflammatory bowel disease (IBD). It is conceivable that reduced intracolonic pH in active ulcerative colitis impairs bioavailability of 5-aminosalicylic acid from pH dependent release formulations (Asacol, Salofalk) and those requiring cleavage by bacterial azo reductase (sulphasalazine, olsalazine, balsalazide), but further pharmacokinetic studies are needed to confirm this possibility. Reports that balsalazide and olsalazine may be more efficacious in active and quiescent ulcerative colitis, respectively, than Asacol suggest that low pH may be a more critical factor in patients taking directly pH dependent release than azo bonded preparations. Reduced intracolonic pH also needs to be considered in the development of pH dependent colonic release formulations of budesonide and azathioprine for use in ulcerative and Crohn's colitis. This paper reviews methods for measuring gut pH, its changes in IBD, and how these may influence current and future therapies.

Effect of octreotide on small intestinal motility in HIV-infected patients with chronic refractory diarrhea.

Octreotide has been used to treat HIV-associated diarrhea. We aimed to assess the effect of octreotide on small intestinal motility in a group of HIV infected individuals with chronic diarrhea. Small intestinal motility was measured continuously for 48 hr by ambulatory strain gauge manometry in 12 HIV seropositive subjects with chronic diarrhea. During the second 24-hr period, intravenous octreotide was administered (100 microg every 8 hr). Postprandial and nocturnal fasting motility data were compared before and during administration of octreotide. Octreotide was associated with increased numbers of migrating motor complexes (MMCs) (7.25 vs 4.92, P = 0.03), and a relative decrease in the duration of phase II (22% vs 49.8, P = 0.03) during nocturnal fasting activity. Postprandial activity was absent in half of the subjects and the duration significantly reduced in the remainder. In conclusion, octreotide has a significant effect on small intestinal motility in HIV-infected individuals with diarrhea, which may influence intestinal transit.

Delayed gastric emptying in human immunodeficiency virus infection: correlation with symptoms, autonomic function, and intestinal motility.

Gastric emptying may be delayed in HIV infection. We aimed to characterize the pattern of gastric emptying in HIV seropositive subjects and correlate the findings with symptoms, as well as to identify possible etiological factors. Solid gastric emptying was measured using scintigraphy in 54 HIV seropositive subjects and 12 HIV seronegative controls. Gastrointestinal symptoms were evaluated using a standardized numerical score, and autonomic function was assessed using spectral analysis of heart rate variability. Fasting and postprandial duodenojejunal activity was recorded using strain gauge manometry catheters. Gastric emptying rate, but not lag phase, was significantly delayed in HIV-infected subjects, particularly those with enteric infections and more advanced disease. Delayed gastric emptying did not correlate with symptoms, autonomic dysfunction, or small intestinal motility. In conclusion, abnormalities found in autonomic function and gastric emptying in HIV infection are multifactorial in nature. The contribution of upper gastrointestinal motor dysfunction to gastric symptoms in such individuals is unclear.

Echoplanar imaging in GI clinical practice: assessment of gastric emptying and antral motility in four patients.

Gastric emptying, frequency of antral contractions, and speed of antral contraction propagation were assessed in four patients using echoplanar imaging techniques. The results obtained and their impact on the diagnosis and management of the patients are presented and discussed. This shows that echoplanar evaluation of gastric function is noninvasive, well-tolerated by patients, detects clinically relevant abnormalities, and has the potential of becoming a valuable examination in the clinical gastrointestinal practice.

The role of the esophagus in dental erosion.

OBJECTIVE: The aim of this study was to measure lower esophageal sphincter pressure, sphincter length, and esophageal motility in patients with dental erosion and compare the results with measurements made in patients without gastroesophageal reflux or dental erosion. STUDY DESIGN: Lower esophageal sphincter length and esophageal motility were measured in 39 patients (age range, 15-74 years) with dental erosion through use of static esophageal pressure monitoring; the data were compared with those from 10 control subjects (age range, 26-46 years) with nonparametric statistical tests. RESULTS: Median lower esophageal sphincter pressure was 9 mmHg (range, 0-26 mmHg) in the patients with erosion and 9.5 mmHg (range, 0 -14 mmHg) in the controls; there was no statistically significant difference between the two subject groups. Similarly, there was no statistically significant difference in esophageal length between the subject groups. There was a statistically significant difference between the groups (P =.01) in the measurement of esophageal motility; the median value was 8% (range, 0% to 100%) in the patients with erosion and 0% (range, 0% to 18%) in the controls. CONCLUSIONS: It appears that esophageal motility in patients with dental erosion is more likely to be associated with low amplitude changes than with sphincter pressure alone. Poor esophageal motility may therefore be a risk factor in regurgitation erosion.

Direct mucosal targeting of colonic receptors by prokinetic drugs in an experimental model.

Isolated perfused segments of pig ileum and sigmoid colon were used as an extrinsically denervated model of intestinal fluid propulsion to compare the effects of intraluminal (IL) with intraarterial (IA) administration of cisapride and mebeverine. The ileal segments had a spontaneous mean activity of 0.008 (SEM 0.003) ml Krebs propelled aborally min-1, with propulsive waves at a mean frequency of 8.3 (1.6) min-1. The sigmoid colon segments ejected a mean of 0.013 (0.009) ml Krebs min-1, with propulsive waves at 3.9 (0.8) min-1. IL cisapride produced a dose-dependent response in the dose range 1 x 10(-9) M to 3 x 10(-1) & 1-3 x 10(-7) M in the ileum, and 3 x 10(-11) to 3 x 10(-9) M in the colonic segments, IL cisapride was significantly more effective than IA delivery of equivalent doses. IL instilled mebeverine (1 x 10(-6) M) inhibited the carbachol dose response of the ileal and colonic segments more than an equivalent dose of mebeverine infused IA. We conclude that the isolated perfused pig intestine is an effective model for studying the pharmacological effects of drugs and their routes of delivery. Cisapride and mebeverine were more effective per given concentration, when delivered IL than IA in both the ileum and sigmoid colon preparations. The qualitative effects of either IL or IA drug delivery were not affected by extrinsic denervation.

An ambulant porcine model of acid reflux used to evaluate endoscopic gastroplasty.

BACKGROUND: There is a lack of suitable models for testing of therapeutic procedures for gastro-oesophageal reflux disease. Endoscopic sewing methods might allow the development of a new less invasive surgical approach to treatment of gastrointestinal disorders. AIMS: To develop an animal model of gastro-oesophageal reflux for testing the efficacy of a new antireflux procedure, endoscopic gastroplasty, performed at flexible endoscopy without laparotomy or laparoscopy. METHODS: At endoscopy a pH sensitive radiotelemetry capsule was sewn to the oesophageal wall, 5 cm above the lower oesophageal sphincter, in six large white pigs. Ambulant pH recordings (48-96 hours; total 447 hours) were obtained. The median distal oesophageal pH was 6.8 (range 6.4-7.3); pH was less than 4 for 9.3% of the time. After one week, endoscopic gastroplasty was performed by placing sutures below the gastro-oesophageal junction, forming a neo-oesophagus of 1-2 cm in length. Postoperative manometry and pH recordings (24-96 hours; total 344 hours) were carried out. RESULTS: Following gastroplasty, the median sphincter pressure increased significantly from 3 to 6 mm Hg and in length from 3 to 3.75 cm. The median time pH was less than 4 decreased significantly from 9.3% to 0.2%. CONCLUSIONS: These are the first long term measurements of oesophageal pH in ambulant pigs. The finding of spontaneous reflux suggested a model for studying treatments of reflux. Endoscopic gastroplasty increased sphincter pressure and length and decreased acid reflux.

Effect of acute dietary fibre supplementation on colonic pH in healthy volunteers.

Dietary fibre and undigested starch are fermented to short chain fatty acids by colonic bacteria with acidification of the colon. It has been suggested that acidification of the colon by these fatty acids inhibits bacterial metabolism, but this concept has been disputed. The aim of this study was to investigate the short term effect of a dietary fibre load on colonic metabolism. Colonic pH and breath hydrogen was measured in healthy omnivorous British male volunteers following ingestion, in turn and at weekly intervals, of 15g lactulose, wheat bran biscuits, oat bran biscuits and ispaghula husk. All the test meals caused a reduction in caecal pH and an increase in breath hydrogen production. The changes were greatest with lactulose. Lactulose and wheat bran caused acidification of the right and left colon whereas oat bran and ispaghula husk caused acidification of mainly the right colon. An inverse correlation between right colonic pH and breath hydrogen was observed in only the oat bran study. This study has demonstrated the ability of dietary fibre to lower right colonic pH and to increase breath hydrogen excretion. The changes were greater with soluble fibre than with insoluble fibre but the change in luminal pH was persistent all round the colon with insoluble fibre.

Effect of chronic dietary fibre supplementation on colonic pH in healthy volunteers.

Dietary fibre supplementations studies to evaluate the effect of dietary fibre on colonic and faecal pH have relied on the use of the unabsorbed disaccharide and osmotic laxative lactulose. We studied the effect of chronic dietary fibre supplementation on colonic pH in healthy British volunteers who consumed a normal mixed diet but who consumed a normal mixed diet but who were asked to double their daily intake of dietary fibre from their usual fibre sources. The median dietary fibre intake of the 5 male volunteers was 17.5 g/day. This was doubled to 34.4 g/day. The pH in all the parts of the colon decreased progressively during the period of study, being lowest at the end of two weeks of fibre supplementation. The pH returned to the presupplementation values within two weeks of cessation of fibre supplementation. This study has shown that the effect of dietary fibre on colonic pH is short-lived and therefore its use for dietary intervention in large bowel diseases should be indefinite.

Physicochemical environment of the colon.

Epidemiological evidence suggests that 80-90% of colorectal cancer is caused by dietary and environmental factors and that the prevalence of cancer can be altered in low-risk patients by long-term alterations in dietary fibre ingestion. It has therefore become increasingly important to examine the available data on colonic pH and transit, and on faecal short-chain fatty acids in different groups, in order to establish the relationship between fibre intake, colonic acidification and the predisposition to cancer in different ethnic groups.

Human small bowel motor activity in response to liquid meals of different caloric value and different chemical composition.

Previous animal studies have shown that the nature and duration of postprandial motility in the small bowel depend both on the caloric load and the chemical composition of a meal. It is not clear whether this is also true for the human small bowel. Therefore we investigated the motor activity of the human small bowel in response to nutrient liquids of different caloric value and different chemical composition. Ten human volunteers underwent three separate, 24-hr ambulatory manometry studies. They drank water, a pure glucose solution, and Intralipid 10% in volumes of both 300 and 600 ml. The caloric value of the nutrient liquids was 330 and 660 kcal, respectively. Records were analyzed visually for the reappearance of phase III of the MMC after ingestion of a test liquid, and a validated computer program calculated the incidence and amplitude of contractions during the postprandial period. Neither duration of the postprandial interval nor the mean incidence or mean amplitude of contractions were different between the fat and the carbohydrate solutions, but phase III reappeared significantly later after ingestion of the nutrient liquids than after water (P = 0.0002). Duration of the postprandial interval also depended on the volume or the caloric load of a liquid meal (P = 0.0012). Mean incidence of contractions tended to be higher after ingestion of nutrient liquids than after water (P = 0.059). We conclude that in ambulant subjects, small bowel motor activity in response to chemically diverse liquid meals is remarkably uniform. This is true for the duration of the postprandial motor activity, as well as the incidence and amplitude of contractions during that period. The caloric value of a liquid meal, however, regulates the duration of the postprandial interval in the human small bowel.

Aetiology of running-related gastrointestinal dysfunction. How far is the finishing line?

30 to 65% of long distance runners experience gastrointestinal (GI) symptoms related to exercise. Several hypotheses have been postulated; however, the aetiology and pathophysiology are far from clear. The mechanical effect of running on the viscera must be involved in the development of GI symptoms in this sport. Reduction of splanchnic blood flow due to visceral vasoconstriction is another widely supported theory; nevertheless, it does not explain many of the clinical findings. Examination of the GI tract during exercise is a difficult task, and measurements of both orocaecal and whole-gut transit time have shown equivocal results. GI hormones, and especially prostaglandins, may be of crucial importance for the production of symptoms. Intestinal absorption, secretion and permeability may also be altered during exercise, provoking intestinal dysfunction. Factors such as stress, diet, dehydration, infections and other factors need to be analysed in order to present a global view of the hypotheses regarding the aetiology of this common and often overlooked problem.