Population genetic screening efficiently identifies carriers of autosomal dominant diseases.

Three inherited autosomal dominant conditions-BRCA-related hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS) and familial hypercholesterolemia (FH)-have been termed the Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a meaningful potential for clinical actionability and a positive impact on public health1. In typical medical practice, genetic testing for these conditions is based on personal or family history, ethnic background or other demographic characteristics2. In this study of a cohort of 26,906 participants in the Healthy Nevada Project (HNP), we first evaluated whether population screening could efficiently identify carriers of these genetic conditions and, second, we evaluated the impact of genetic risk on health outcomes for these participants. We found a 1.33% combined carrier rate for pathogenic and likely pathogenic (P/LP) genetic variants for HBOC, LS and FH. Of these carriers, 21.9% of participants had clinically relevant disease, among whom 70% had been diagnosed with relevant disease before age 65. Moreover, 90% of the risk carriers had not been previously identified, and less than 19.8% of these had documentation in their medical records of inherited genetic disease risk, including family history. In a direct follow-up survey with all carriers, only 25.2% of individuals reported a family history of relevant disease. Our experience with the HNP suggests that genetic screening in patients could identify at-risk carriers, who would not be otherwise identified in routine care.

An investigation into the efficacy of the pectin based anti-reflux formulation-Aflurax.

The properties of the new pectin-based anti-reflux agent Aflurax (Ferrosan) were studied in vitro and in vivo. Aflurax had a significantly higher in vitro raft strength than the placebo which was matched to the active except for the pectin (4.66+/-2.10 and 0. 22+/-0.04 g, respectively). In the modified Rossett and Rice test, the pectin raft remained above pH 3 for 130 min, whereas the pH in the acid phase remained unchanged. A modification to the stirring speed of the Rossett and Rice test was required to obtain a neutralisation profile for the placebo. The neutralisation profiles for the Aflurax and placebo were the same since both contained 5 mEq of base per tablet. In the in vivo study, subjects were randomly assigned to two groups, which either received radiolabelled food and unlabelled formulation, or unlabelled food and radiolabelled formulations. A pH probe was passed naso-gastrically and placed 5 cm from the cardia, and a small gamma detector was placed on the chest wall, coincident with the pH probe. The subjects received the test meal after an overnight fast. The pectin formulation or placebo was administered 30 min later. Each part of the study was performed as a single-blind two-way cross over with the active versus placebo. The reflux of radiolabel and acid was monitored for three hours postprandially. Aflurax reduced the H(+) concentration (total refluxed hydrogen ion index for Aflurax=3.5 x 10(3)+/-2.1 x 10(3), placebo=29 x 10(3)+/-16 x 10(3)) and amount of radiolabelled food reaching the oesophagus (total refluxed count index of food in counts x 1000 min(-1) Aflurax=19.2+/-2.3, placebo=525+/-423). The mean time for which the oesophageal pH fell below pH 4 was 2.58+/-1. 0 and 0.86+/-0.4 minutes for the placebo and Aflurax groups, respectively. The total amount of radiolabelled formulation which reached the oesophagus was 1000+/-660 for the placebo and 621+/-580 for the Aflurax.

Effect of resin surface charge on gastric mucoadhesion and residence of cholestyramine.

Previous studies performed on excised gastric tissue and in healthy volunteers revealed that the ion exchange resin, cholestyramine, exhibits mucoadherent behaviour. This study was designed to elucidate whether surface charge affected this behaviour. Gamma scintigraphy was performed on fasted normal subjects following oral administration of cholestyramine or the cationic exchanger Amberlite(R) IRP-69, either uncoated or polymer-coated to mask their charge. Subjects were fed after 4 h. The initial gastric emptying of all formulations was similar (T(50) values (mean+/-S.E.M.): cholestyramine=85.86+/-9.16 min; IRP-69=76.09+/-9.23 min; polymer-coated cholestyramine=72.0+/-12.64 min; polymer-coated IRP-69=70.25+/-10.57 min: P=0.724). However, after 3 h the emptying pattern of cholestyramine was slower than that of IRP-69. This resulted in greater retention times than IRP-69 (AUC(0-6) values (relative units)=15,200+/-1093 versus 9452+/-811; cholestyramine versus IRP-69: P=0.0004). This effect was reduced by polymer-coating the cholestyramine. Serial images showed that cholestyramine was trapped in the oropharyngeal region and subsequently displaced by the meal, resulting in higher levels of activity remaining at 6 h. Thus, cholestyramine exhibited prolonged gastric residence via mucoadhesion and was distributed throughout the stomach. The surface charge of the resin was found to have a contributory role. These materials may have potential for the delivery of drugs in the topical treatment of the gastric mucosa, for example in the eradication of Helicobacter pylori.

The effect of nasal patency on the clearance of radiolabeled saline in healthy volunteers.

PURPOSE: The objective of this study was to investigate the effect of nasal cavity patency on the penetration, deposition, and clearance of an aqueous isotonic saline solution. METHODS: The study was carried out as a single center, open, randomized, 2-way cross-over in healthy volunteers. Nasal patency was assessed using misting patterns on a cold metal surface at the beginning and end of study. 100 microl of technetium-99m radiolabeled saline solution was introduced into either the most or least patent nasal cavity using a purpose designed spray device. The distribution and residence time of the radiolabel was followed for 2 hours using gamma scintigraphy. RESULTS: The mean times to 50% clearance were 34+/-7 and 28+/-12 minutes (+/- s.d.) for the side view of the least and most patent nasal cavity respectively. Total clearance of the radiolabelled saline from the nose was not affected by patency. Between 7 and 35% of the radiolabelled saline solution remained in the nasal cavity at the end of imaging. Using endoscopy to track the clearance of an aqueous solution of food dye using the same delivery procedure, identified this region as hair in the nasal vestibule. The dye was seen to dry in this region along with the mucus. CONCLUSIONS: Nasal patency affects the initial, but not total clearance of solutions, however, the remaining solution may not be available for drug delivery.

Determination of baseline human nasal pH and the effect of intranasally administered buffers.

The nose is becoming a common route of drug administration, however, little is known about the pH of the human nasal cavity. Local pH may have a direct effect on the rate and extent of absorption of ionizable compounds and hence this study was performed to investigate normal pH values and whether pH could be manipulated by various buffers. Twelve healthy volunteers participated in a study to measure pH in the anterior and posterior sites of the nasal cavity. Miniature pH electrodes were placed 3 cm apart in the nasal cavity and a baseline was recorded for 30 min once the pH had stabilized. One hundred microlitres of isotonic solution was sprayed into the nostril and the pH was measured for 4 h post-dose. The following five formulations were tested: formulation A--sodium chloride (0.9%) at pH 7.2; formulation B--sodium chloride (0.9%) at pH 5.8; formulation C--Sorensens phosphate buffer (0.06 M) at pH 5. 8; formulation D--Sorensens phosphate buffer (0.13 M) at pH 5.8 and formulation E--formulation as (c) but adjusted to pH 5.0. Each formulation also contained saccharin sodium (0.5%) as a taste marker for nasal clearance. The time at which each subject detected the taste of saccharin was noted. The 30-minute baseline recording prior to administration of the nasal spray formulation demonstrates that there was both considerable intersubject and intrasubject variation in nasal pH. The average pH in the anterior of the nose was 6.40 (+0. 11, -0.15 S.D.) when calculated from H(+) values. The pH in the posterior of the nasal cavity was 6.27 (+0.13, -0.18 S.D.). The overall range in pH was 5.17-8.13 for anterior pH and 5.20-8.00 for posterior pH. Formulation A caused the pH in the anterior part of the nasal cavity to reach a maximum of 7.06 in 11.25 min from the baseline of pH 6.14 (P<0.05). The mean baseline pH was 6.5 for the posterior part of the nose which did not change over the recording period. Formulation B caused the anterior pH to increase from pH 6. 60 to 7.25 within the first minute. This fell back to a mean pH of 7.07 over the first hour which was still significantly above the baseline. It remained at this value for the remainder of the recording period. The initial average posterior pH was 6.32 and again this did not significantly change over the recording period. Formulation C produced a sustained increase in anterior nasal pH from a baseline pH of 6.57-7.12. A small transient decrease was observed in the pH in the posterior of the nose but baseline pH of 6. 6 was re-established within 15 min post dose. Formulation D significantly reduced anterior nasal pH from 6.30 to 5.87 by 30 min reaching a pH of 5.95 by 90 min where it remained for the remainder of the recording period. The posterior baseline pH was 6.3 and introduction of the pH 5.8 buffer caused a slow increase over 90 min to pH 6.6. Formulation E increased anterior pH from 6.1 to 6.7 for the remainder of the recording period. It had an insignificant effect on posterior nasal pH. The mean (+/-S.D.) time to taste saccharin for formulations A to E was 13.42+/-10.21, 14.67+/-8.37, 11.67+/-8.08, 10.08+/-7.6, 9.80+/-6.73 min, respectively. There was no significant difference between the clearance times for the different formulations. In conclusion, average baseline human nasal pH is approximately 6.3. Nasal anterior pH can be decreased when buffers of 0.13 M and above are used. Mildly acidic solutions produce an increase in pH presumably due to reflux bicarbonate secretion. Posterior nasal pH was not altered by administration of any buffer except the 0.13 M buffer at pH 5.8. This produced a rise in posterior pH.

Dry powder dosing in liquid vehicles: ocular tolerance and scintigraphic evaluation of a perfluorocarbon suspension.

The ocular tolerance and precorneal disposition of 99mTc-labelled sterile carbon-perfluorodecalin (PFD) and carbon-aqueous suspensions were examined in a cohort of healthy volunteers. Formulations were prepared in PFD or saline using charcoal particles, radiolabelled with [99mTc]diethylenetriaminepentaacetic acid (DTPA) under GMP conditions. Colloidal silicon dioxide was used as a suspending agent. Ocular tolerance was examined following the instillation of each formulation to the eyes of 12 volunteers. The precorneal distribution of both formulations in man was monitored using gamma scintigraphy. Dynamic and static data acquisitions were taken over a period of 150 min after dosing. Carbon particulates suspended in PFD did not show any irritation to the eye. Administration of PFD formulation in man produced a significant increase in ocular retention over a saline formulation (mean residence time (MRT)=157+/-42 and 0.29+/-0.08 min, respectively, P=0.0001). Distribution of the carbon in man followed the same pattern as in a previous reported study in animals. The carbon deposited uniformly along the lid margin in the case of the PFD vehicle, whereas it agglomerated following dosing in the saline vehicle and was ejected from the eye. The novel non-aqueous vehicle system is able to significantly improve the ocular retention of charcoal particles in man and provides a unique distribution of the particles in the eye, which suggests a potential for the PFD system for the treatment of periocular diseases.

Dual pH probe monitoring versus single pH probe monitoring in infants on milk feeds: the impact on diagnosis.

OBJECTIVES: Oesophageal pH monitoring is the gold standard technique for the detection of gastro-oesophageal reflux in adults and children. A standard parameter used to define "abnormal" reflux is the percentage of recording time for which the gastric pH is < 4. This study investigated the relevance of this measure in infants on regular milk feeds whose gastric contents and refluxate will be neutral for most of the recording time. METHODS: Simultaneous oesophageal and gastric pH monitoring was carried out on all infants who were milk fed exclusively and admitted to hospital for suspected gastro-oesophageal reflux. In vitro studies were performed to establish the buffering capacities of the fruit juice, Dioralyte (a glucose electrolyte solution), breast milk, and milk formula feeds available on the paediatric wards. RESULTS: Complete sets of data were obtained from 30 babies with a mean age of 4 months. Gastric pH was 4 increased this value to 17.81 (2. 46)%. Using a cut off point of 10%, 11 of the 30 babies would have been diagnosed positive for reflux using the conventional method; however, recalculation by ignoring the time for which gastric pH was high doubled this to 22 positive for reflux. CONCLUSION: Combined oesophageal and gastric pH monitoring greatly increases the number of positive results from tests in infants on regular milk feeds.

Twenty-four hour ambulatory nasal pH monitoring.

The nasal delivery of drugs, both for systemic and local use, is an expanding field with many drugs being delivered by this route. It is known that changes in pH can affect drug absorption but there is no data regarding intranasal pH over time. We present the results of 24-h ambulatory nasal pH monitoring in four subjects, each of whom had monitoring on two separate occasions. The apparatus consisted of a pH monitor with two electrodes, thus enabling us to take readings from 1 and 4 cm behind the anterior end of the inferior turbinate. Measurements were recorded every 6 s by the posterior electrode and every 30 s by the anterior electrode. The recording apparatus was worn around the subjects waist. Analysis of the results showed that there was no diurnal variation and no significant differences between the subjects. The mean pH from the anterior electrode was higher than that from the posterior (7.1 versus 6.6). The pH did not fluctuate with daily activities such as eating, drinking or sleeping. The results are interesting and may be of importance with regard to the design of formulations for nasal drug delivery systems.

Patterns of food and acid reflux in patients with low-grade oesophagitis--the role of an anti-reflux agent.

BACKGROUND: Food and acid have been shown to be refluxed independently of each other in healthy volunteers, and anti-reflux agents decrease the reflux of both parameters. Until now this phenomenon had not been studied in patients with low-grade oesophagitis, who are the group most likely to use anti-reflux medication. AIM: To assess patterns of gastro-oesophageal reflux of acid and food in 12 ambulant patients with endoscopically proven oesophagitis of between grades I and II, but who were otherwise healthy. Also to assess the effectiveness of a single dose of an alginate-containing anti-reflux agent in controlling food and acid reflux in this patient group. METHODS: Oesophageal pH monitoring and external ambulatory gamma detection were used to study food and acid reflux. A pH electrode was positioned 5 cm above the cardia and the gamma detector was positioned externally over the pH electrode. The patients then received a technetium-99m labelled meal designed to provoke reflux. Thirty minutes later the patients were given a 20 ml dose of alginate (Liquid Gaviscon), or 20 ml of tap water. Incidence of reflux was monitored for approximately 4 h from the end of the meal. Allocation to treatment group was randomized, with patients receiving the alternative treatment on the second study day after approximately a 7-day washout period. RESULTS: The mean percentage time oesophageal pH remained below 4 was 16.3 min for the control group and 5.4 min for the treatment group (P = 0.03). Food reflux was detected 23.7% of the time in the control group compared to 12% of the time in the treatment group (P = 0.02). The anti-reflux agent was also successful in decreasing the number of events, but the duration of the reflux events was not significantly different. CONCLUSIONS: Patients with grades I and II oesophagitis reflux food and acid independently, and are predominantly either food refluxers or acid refluxers, but not both. Liquid alginate decreases the number of both food and acid reflux events, but does not change their duration.

Mebeverine decreases mass movements and stool frequency in lactulose-induced diarrhoea.

BACKGROUND: In spite of its frequent use in the treatment of irritable bowel disease little is known about mebeverine's mode of action in man. AIM: To examine mebeverine's effect on transit though the gut during lactulose-induced diarrhoea. METHODS: Nine healthy volunteers undertook a two-way randomized crossover study. Diarrhoea was induced using lactulose pre-treatment (20 m t.d.s., 4 days) and subjects received either mebeverine (135 mg t.d.s.) or no treatment. Transit of two enteric-coated capsules containing radiolabelled 8.4 mm tablets and 180-250 microM ion exchange resin were followed using gamma scintigraphy. Stool frequency and symptoms were assessed by diary cards. RESULTS: Mebeverine reduced mean daily stool frequency associated with lactulose ingestion from a median of 2.25 (interquartile range (IQR) 1.75-2.75) to 1.5 (IQR 1.25-2.25) movements. Mebeverine significantly reduced the number of mass movements observed in the colon during the 11 h of the study from 2 (2-2) to 1 (1-2), and the number of retrograde movements from 1 (0-2) to 0 (0-0) (P < 0.05). Mebeverine did not significantly alter the gastric emptying rate of the intact capsule (2.9 (1.9-3.2) to 2.8 (2.6-4.0) h) however it induced a small but significant acceleration in small intestinal transit of the capsule (1.6 (0.8-2.0) h to 1.0 (0.52-1.32) h, P=0.02). CONCLUSION: Mebeverine reduces the diarrhoeal effect of lactulose by decreasing the mass movements induced in the ascending colon. This effect may contribute to its clinical effect in irritable bowel syndrome.

[The effect of pretreatment with ranitidine on the pharmacokinetics and gastrointestinal transit of a sustained-release theophylline preparation]. / Wirkung der Vorbehandlung mit Ranitidin auf Pharmakokinetik und gastrointestinale Passage eines Theophyllin Retard-Präparates.

A scintigraphic and pharmacokinetic study of the behavior of Bronchoretard forte (theophylline, CAS 58-55-9) was carried out in 8 healthy male volunteers to evaluate the sensitivity of the preparation to changes in gastric pH. The volunteers were pretreated with ranitidine (CAS 66357-35-5) (150 mg b.i.d.) or placebo for three days prior to and on the study day to reduce gastric acidity. The effect of the pretreatment with ranitidine on gastric pH was measured on the day before study begin and the mean pH was significantly increased compared to the placebo (ranitidine pH 2.2 +/- 2.4; placebo pH 1.6 +/- 2.0, p < 0.01 Wilcoxon Signed Rank test). All subjects were pretreated with theophylline for 3 days (500 mg b.i.d.) to achieve steady state. On the study day, the volunteers swallowed two theophylline sustained release capsules, radiolabelled by inclusion of indium-111 micronised Amberlite resin, and the gastrointestinal transit was followed continuously for 14 h using gamma scintigraphy with a further image at 24 h. Blood samples were taken from each subject throughout the study to determine the pharmacokinetic profile of theophylline in the sustained release formulation. No significant differences were found in the gastrointestinal transit of the labelled microparticulates between the data obtained from the group treated with ranitidine and that from the placebo group. Plasma theophylline concentration profiles were identical for the two treatments. These data indicate that the theophylline sustained release formulation is not sensitive to the effects of major changes in gastric H+ concentration.

Moderation of lactulose-induced diarrhea by psyllium: effects on motility and fermentation.

Psyllium has been reported to inhibit lactulose-induced colonic mass movements and to benefit patients with irritable bowel syndrome, improving both constipation and diarrhea. Our aim was to define how psyllium modified the whole-gut transit of a radiolabeled lactulose-containing test meal by using gamma scintigraphy. Eight subjects participated in a randomized crossover study comparing gastric emptying and small bowel and colonic transit after consumption of 20 mL lactulose three times daily with or without 3.5 g psyllium three times daily. Psyllium significantly delayed gastric emptying: the time to 50% emptying increased from a control value of 69 +/- 9 to 87 +/- 11 min (mean +/- SEM; P < 0.05, n = 8). Small bowel transit was unaltered. However, progression through the colon was delayed with an increase in the percentage of the dose at 24 h in the ascending (control group: 2 +/- 3%, psyllium group: 11 +/- 8%; P < 0.02) and transverse colon (control group: 5 +/- 12%, psyllium group: 21 +/- 14%) with correspondingly less in the descending colon. Although the time for 50% of the isotope to reach the colon was not significantly different with psyllium, psyllium significantly delayed the rise in breath-hydrogen concentrations, which reached 50% of their peak at 217 +/- 34 min compared with control values of 155 +/- 27 min (P < 0.05). Psyllium delays gastric emptying, probably by increasing meal viscosity, and reduces the acceleration of colon transit, possibly by delaying the production of gaseous fermentation products.

An investigation of lower oesophageal redox potentials in gastro-oesophageal reflux patients and healthy volunteers.

Oesophageal electrical properties are thought to be important in the development of gastro-esophageal reflux. This study simultaneously monitored the intraoesophageal pH and redox potentials in 18 patients with gastro-oesophageal reflux symptoms and 15 asymptomatic controls, for a 24 h period. The pH and redox electrodes were positioned 5 cm proximal to the lower oesophageal sphincter, the position of which had been determined by manometry. Since significantly different behaviour was observed during the day and night, the data were divided into periods of waking and sleeping. Data were analysed for acid reflux (pH < 4) and transients in the redox potential-time curve. Both patients and normal subjects showed negative redox transients which were more frequent and pronounced at night than during the day, and which were uncorrelated with acid reflux. The only parameter which was significantly different between normal and refluxing groups was the amount of nocturnal redox activity, which was lower in refluxing subjects than in normals. Some possible hypotheses for these observations, and the origin of the redox species, are discussed.

Using CAI to accommodate a variety of learning styles in a biomechanics course.

Multimedia technology offers a more interactive approach to instruction than the traditional classroom lectures. Through computer-aided instruction (CAI), a number of teaching styles can be used that take into account the different preferences of the students. The Biomechanics Tutorial program that the authors have written is a CAI that incorporates audio, video, simulations, and graphics to: review concepts of mechanics (kinematics and kinetics of interconnected rigid bodies), familiarize students with functional anatomy, and allow students to interactively evaluate the law of mechanics applied to physical performance of activities modeled by a set of biomechanical models of the joints. Principles of ergonomics are reinforced by enabling the student to perform numerous numerical experiments within the context of workplace or task redesign and see the real time consequences of these alterations. For example, the task of holding a load is simulated by allowing the student to change elbow and shoulder angles and the orientation and magnitude of the load. The consequences of these in terms of required muscle forces and joint reaction forces at the elbow and shoulder will be updated on the screen. The detailed rationale of developing this Biomechanics Tutorial which integrates a variety of learning styles will be presented.

Effect of alginate and alginate-cimetidine combination therapy on stimulated postprandial gastro-oesophageal reflux.

This randomized, single-blind cross-over study compared the effectiveness of a conventional alginate reflux barrier formulation (20 mL single dose of Liquid Gaviscon; sodium alginate, sodium bicarbonate, calcium carbonate) with a 20 mL single dose of an alginate-cimetidine combination formulation (Algitec Suspension; sodium alginate, cimetidine) in the suppression of food and acid reflux into the oesophagus after a test meal in 12 healthy volunteers. Subjects were fasted overnight before the study. A pH electrode and gamma detector were accurately positioned 5 cm above the cardia. The volunteers received a 99mTc-labelled meal designed to provoke reflux and then either remained untreated, or 30 min later were given either Algitec Suspension or Liquid Gaviscon. Reflux of both food and acid into the oesophagus was measured for 3 h. There was a seven day wash-out period between each treatment. Food reflux in the control group was 22,878 +/- 14,385 counts x 10(3) and this was significantly suppressed by both Liquid Gaviscon (174 +/- 128 (s.e.) counts x 10(3); P = 0.003); however, although the reduction of food reflux to 3812 +/- 2322 counts x 10(3) observed after Algitec treatment was considerable, this did not reach statistical significance (P > 0.05) due to the large intersubject variation. Liquid Gaviscon was significantly better at reducing food reflux than Algitec (P = 0.001). Gaviscon also significantly reduced acid reflux when compared with the control group (1.08 +/- 0.73 vs 5.87 +/- 3.27% recording time oesophageal pH < 4, respectively) (P = 0.03). The slight reduction in acid reflux after Algitec treatment (3.25 +/- 1.82% recording time oesophageal pH < 4) also did not reach statistical significance. The difference between Algitec and Gaviscon treatment was also not significant.

Intragastric distribution of ion-exchange resins: a drug delivery system for the topical treatment of the gastric mucosa.

Previous studies by this group on freeze-dried oral dosage forms containing finely-divided ion-exchange resins revealed prolonged gastric residence and uniform distribution within the stomach. The present study was carried out to ascertain whether this was due to freeze-drying, properties of the radiolabelled ionic exchange resin, or the small dosing volume used. 99mTc-labelled cholestyramine resin was administered in two dosage forms, a freeze-dried tablet which dissolved in the oral cavity (orally dissolving tablet; ODT) and a 1.5 mL aqueous suspension. Two resin particle sizes (20-40 and 90-125 microns) were studied. Oesophageal transit and intragastric distribution and residence were followed by gamma scintigraphy. In a second study, in six subjects, gastric emptying of the water-soluble fraction of the ODT and 1.5 mL of water, was measured using 99mTc diethylenetriaminepentaacetic acid. Oesophageal transit of a water-soluble marker and resin in suspension was rapid, but the transit of the resin in the ODTs was significantly prolonged. Regardless of particle size or dosage form, the resin was evenly distributed throughout the stomach with 20-25% remaining for 5.5 h. In contrast, the water-soluble marker cleared from the stomach rapidly from both dosage forms. We suggest that oral dose forms containing finely-divided ion-exchange resins may form a useful system for topical treatment of the gastric mucosa, for example in targeting to Helicobacter pylori infection.

Effect of a test meal on the intragastric distribution of urea in the 13C-urea breath test for Helicobacter pylori.

Test meals are invariably used in the 13C-urea breath test (UBT) but their effect on the intragastric distribution and gastric residence time of urea given in the test is unknown. The site of Helicobacter pylori urease measured in the test is unknown and whether the test measures total or regional gastric urease is uncertain. This study reports the results of paired UBTs with simultaneous gastric distribution studies, one with and one without a fatty test meal, two weeks apart on seven H pylori infected subjects. The test meal did not affect UBT results at 10 minutes, but increased values at 30 minutes and thereafter. The amount of scintigraphic label in the antrum at 10 minutes was also unaffected by the meal but increased at 30 minutes and thereafter, whereas the amount in the body/fundus was greatly increased both at 10 minutes and throughout the test. There was considerable variation in intragastric distribution of urea between subjects, both with and without the test meal. This study shows that a test meal profoundly affects intragastric distribution of urea solution in the UBT, and increases UBT values at 30 minutes and later. Variability between subjects, however, means that accurate measurement of total or regional gastric urease is probably unrealistic.

The effect of pectin on the gastric emptying rates and blood glucose levels after a test meal.

This study was designed to evaluate the effect of pectin given in a palatable form on the gastric emptying rates of the solid and liquid phases of a test meal and to ascertain whether pectin affected blood glucose levels in ten healthy male and female volunteers. Gastric emptying was measured using dual isotope gamma scintigraphy. Allocation to the treatment group was double-blind and randomized. Sequential blood sampling was used to measure blood glucose levels. The times for the stomach to empty half the radiolabelled meal were similar after both pectin and placebo; however, a significant difference was seen between the AUC values of the meal between the two treatments. This can be attributed to the divergence of the emptying curves after the time point at which 50% of the meal had emptied, as pectin delayed the emptying of the last 20% of the meal. The initial phase of emptying for both pectin and placebo was significantly faster than the meal. No significant difference was found between blood glucose levels when either pectin or placebo was administered.

Scintigraphic assessment of the intragastric distribution and gastric emptying of an encapsulated drug: the effect of feeding and of a proton pump inhibitor.

BACKGROUND: Local delivery of therapeutic agents to the stomach may be a useful strategy in the treatment of Helicobacter pylori infection. We aimed to see whether the intragastric distribution and gastric retention of a therapeutic agent could be improved, either by giving omeprazole or by dosing after a meal. METHODS: Twelve healthy volunteers took part in this double-blind placebo-controlled crossover study comparing the effects of omeprazole 20 mg twice daily for 5 days with placebo, and the fasted with the fed state, on the gastric emptying and intragastric distribution of a soluble scintigrapic marker contained in a drug capsule. RESULTS: Dosing after food profoundly prolonged gastric residence of the drug label, prolonging mean time to 50% emptying (T50) from 0.5 +/- 0.1 h in the fasted state to 2.0 +/- 0.2 h when given after food. Food also improved intragastric distribution by increasing delivery to the body and fundus. Omeprazole enhanced the effect of food, prolonging T50 to 2.9 +/- 0.3 h, but had no effect in fasted subjects. CONCLUSIONS: Dosing after food markedly improves the aspects of local drug delivery to the stomach investigated in this study, and omeprazole enhances this effect. Post-prandial dosing may, therefore, be useful for improving delivery of some anti-Helicobacter agents.

Non-invasive detection of gastro-oesophageal reflux using an ambulatory system.

The aim of this study was the separate measurement of reflux of food and acid into the oesophagus in 37 healthy, ambulant subjects. This was performed by radiolabelling the food and monitoring its reflux with a small directional gamma detector, which was placed externally over the oesophagus, and connected to an ambulatory data recorder. The pH was measured with a conventional oesophageal pH electrode. This method permitted the separate characterisation of acid and neutral (food) components of gastro-oesophageal reflux. The gastric emptying characteristics of the test meal were also monitored by gamma scintigraphy in a separate experiment. The oesophageal pH fell below 4 for 3.2 + 8.6/-2.3% (mean (SD)) of the recording time. Food reflux alone occurred for 17.8 + 53.2/-13.8% of the recording time. Simultaneous food and acid reflux occurred for only 0.95 + 5.2/-1.2% of the time. Not every reflux event detected by a fall in pH was seen as an increase in counts as a result of reflux of food, and vice versa. This poor correlation of food and acid reflux implies incomplete mixing of food and acid in the stomach, and further shows the inadequacy of reflux diagnosis methods that depend on pH detection alone.