Magne Alpsten

Drug absorption from nifedipine hydrophilic matrix extended-release (ER) tablet-comparison with an osmotic pump tablet and effect of food.

The aim of the present study was to compare the bioavailability of nifedipine when administered as a hydrophilic matrix tablet (ER) and a push-pull osmotic pump tablet (XL) administrated after fasting, and to evaluate the effect of food for the hydrophilic matrix tablet. For this purpose, three separate studies were performed on healthy volunteers (n = 58) including gammascintigraphic monitoring of tablet erosion and localisation in the gastrointestinal tract for ER in one study. Both ER and XL provided almost constant drug delivery over 24 h, after administration under fasting conditions, and bioequivalence was obtained according to 90% confidence intervals of the difference between formulations within 80-125% for Cmax and AUC. Food significantly increased AUC for ER but no significant difference was obtained between ER and XL with food with respect to extent of bioavailability. The rate of absorption was increased to a higher degree for ER than for XL, as indicated by a Cmax which was almost twice as high for ER compared with XL. This finding was shown to be related to an increased tablet-erosion rate for ER, leading to more rapid drug release.

Gastro-intestinal transit of a multiple-unit formulation (metoprolol CR/ZOK) and a non-disintegrating tablet with the emphasis on colon

Abstract The main aim of the present study was to compare the transit through the entire gastro-intestinal channel of a membrane-coated, multiple-unit system containing metoprolol and a single-unit placebo tablet using gamma-scintigraphy. The two formulations were simultaneously administered, together with a breakfast (2800 kJ), to eight healthy male volunteers. The mean gastric emptying time for the pellets was 3.6 (range 1.5–5.0) h on average and the mean gastric emptying time for the tablet was 9.6 (range 3.3-(14–24)) h. This difference was statistically significant. The mean transit through the small intestine, 3.1 (range 1.5–5.7) h and 2.0 (range 1.0–3.3) h for the pellets and the tablet respectively, did not differ significantly between the formulations. The pellets had a longer residence time in the colon in all subjects compared with the tablet. The mean colon transit time was 28 (range 6.0–48) h on average for the pellets and 15 (range 3.8–26) h for the tablet. The tablet was expelled 26 (range 9.5–42) h after intake on average, whereas the pellets remained for a significantly longer time period (mean 35, range 10–55 h). The desired extended-release properties and metoprolol absorption was obtained throughout the entire gastrointestinal (GI) tract.

In vitro and in vivo erosion of two different hydrophilic gel matrix tablets

The aim of the present work was to establish in vivo predictive in vitro tests for the tablet erosion of two different compositions (A and B) of hydrophilic matrix tablets based on hydroxypropyl methylcellulose. The tablet erosion was studied in a modified USP II apparatus at different agitation intensities and ionic strengths according to 2(2) factorial design. The in vivo tablet erosion was studied in 8 healthy human volunteers by gamma scintigraphy after administration of the tablets together with breakfast. In vitro agitation intensity increased the erosion rate for both tablets whereas increased ionic strength caused a slower rate for tablet A and a faster rate for tablet B. The choice of in vitro testing conditions proved to be critical for the attainment of in vivo predictive results. The best in vitro/in vivo correlation for the two formulations was obtained at a paddle stirring rate of 140 rpm and a ionic strength of 0.14 obtained by addition of sodium chloride.

Small particle size of a solid meal increases gastric emptying and late postprandial glycaemic response in diabetic subjects with gastroparesis

Our goal was to investigate if food of small particle size increases the gastric emptying rate and lessens the fall in postprandial blood glucose in seven subjects with Type 1 diabetes and gastroparesis. Two solid meals of identical composition but of different particle size, with 5MBq (99m)Tc added to the meals, were ingested in randomized order in seven subjects with Type 1 Diabetes Mellitus and gastroparesis and seven healthy subjects. During 180min blood glucose and insulin concentrations were measured and gastric emptying of the ingested meals was registered by a gamma camera. The lag phase in the stomach was significantly shorter, the radioactivity remaining in the stomach after 120min (T(120)) was significant less and the postprandial blood glucose dip was less and of shorter duration after a small particle (SP) meal, compared to a large particle (LP) meal in diabetic subjects. Gastric emptying did not differ significantly between groups after an SP meal. Food of small particle size increases the gastric emptying rate and reduces the postprandial blood glucose dip in both magnitude and duration in Type 1 diabetic subjects with gastroparesis, which is likely to be of importance in achieving good metabolic control.

The Effect of Parietal Cell Vagotomy and Selective Vagotomy with Pyloroplasty on Gastric Emptying of a Solid Meal: A Prospective Randomized Study

A new technique is described whereby gastric emptying of a 51Cr-labelled solid meal (hamburger, vegetables, potatoes) was measured by way of a movable NaJ(T1) detector. The technique allowed separate measurements over the proximal and the distal part of the stomach. Seven volunteers took part in a study which revealed good correlation between two individual consecutive tests. Eight patients who took part in a controlled randomized series of parietal cell vagotomy (PCV) versus total gastric selective vagotomy and pyloroplasty (SV+P) underwent the test preoperatively and 6 to 8 months postoperatively. Following both operations gastric emptying was retarded. The time taken for the amount of meal remaining in the stomach to be reduced to 75,50 and 25% respectively was significantly longer postoperatively than before surgery, but there were no differences in this respect between PCV and SV+P. The retardation of gastric emptying of solids was in contrast to the emptying of 10% glucose solution, which in the same series of patients was found to be accelerated. Following PCV there was a change in the distribution of the meal within the stomach immediately after the intake of the meal: a larger part of the meal was found in the proximal stomach post-operatively than before operation. There was no significant change in this intragastric distribution of the meal after SV+P.

Gastrointestinal Transit of Amoxicillin Modified-Release Tablets and a Placebo Tablet Including Pharmacokinetic Assessments of Amoxicillin

BACKGROUND We have investigated the gastrointestinal transit time of, the influence of food intake on, the disintegration of, and the pharmacokinetics of amoxicillin in a modified-release form. METHODS Radiolabelled modified-release tablets of amoxicillin and placebo tablets were administered, in an open three-way, randomized, crossover design, as single doses during omeprazole treatment, to six male healthy subjects during fasting and non-fasting conditions. Radioscintigraphic images and plasma samples were obtained. RESULTS The estimated mean (and range) gastric emptying time of the modified-release tablet after drug administration was 0.3 h (0.1-1.0 h) during fasting conditions, 4.3 h (1.7-5.0 h) after a light breakfast, and 4.9 h (1.9-18.0 h) after a heavy breakfast. The small-intestinal transit time during fasting conditions was 4.7 h (2.9-6.9 h) and was not significantly changed after light or heavy breakfast intake. The relative bioavailability of the modified-release tablet was 55%, compared with a commercially available amoxicillin immediate-release tablet. CONCLUSION The modified-release tablet of amoxicillin administered postprandially apparently increases the amoxicillin release time in the stomach. The relevance of its use for anti-H. pylori treatment can be questioned.

Dose reduction for body composition measurements with CT

The purpose was to obtain reliable measures of fat and muscle tissue areas with CT at a reduced radiation dose level. Repeated CT-scans with four different levels of reduced radiation dose were perfomed on a water phantom and a volunteer at the L4-L5 level. Dose measurements were performed in a phantom and free in air. A histogram model function for fat, muscle and partial volume affected voxels was proposed and used in the analysis of image noise. The result was at most a 25-fold reduction in radiation dose with an image noise of 40 HU but only a minor influence on the tissue area determination [corrected].

A comparison of different methods to measure body composition in patients

A comparison of different methods to measure body composition in growth hormone deficient patients is presented. The technical limitations of the available methods are discussed. The techniques used to measure body composition and fat free mass has been by total body water, total body potassium, dual energy X-ray absorptiometry, bioelectrical impedance and total body nitrogen.

Extended ISIS sequences insensitive to T1 smearing

Image selected in vivo spectroscopy ( ISIS ) is a volume selection method often used for in vivo 31P MRS, since it is suitable for measurements of substances with short T2. However, ISIS can suffer from significant signal contributions caused by T1 smearing from regions outside the VOI. A computer model was developed to simulate this contamination. The simulation results for the ISIS experiment order implemented in our MR system (ISIS‐0) were in agreement with results obtained from phantom measurements. A new extended ISIS experiment order ( E‐ISIS ) was developed, consisting of four “optimal” ISIS experiment orders (ISIS‐1 to ISIS‐4) performed consecutively with dummy ISIS experiments in between. The simulation results show that contamination due to T1 smearing is, effectively, eliminated with E‐ISIS and is significantly lower than for ISIS‐0 and ISIS‐1. E‐ISIS offers increased accuracy for quantitative and qualitative determination of substances studied using in vivo MRS. Hence, E‐ISIS can be valuable for both clinical and research applications. Magn Reson Med 44:546–555, 2000.

Signal profile measurements of single- and double-volume acquisitions with image-selected in vivo spectroscopy for 31P magnetic resonance spectroscopy

The volume-selection performance was studied for single- and double-volume-of-interest (VOI) acquisition with the volume-selection method image-selected in vivo spectroscopy for 31P magnetic resonance spectroscopy. High-resolution signal profiles were measured using a phantom simulating a brain. Inside the phantom there was a small, remotely controlled, movable signal source filled with ortho-phosphoric acid. Signal profiles of the VOI were measured in three perpendicular directions for 1VOI (single VOI) and 2VOI (double VOI) acquisition. The measured signal profiles for both acquisitions were very similar, but they showed a discrepancy with regard to the intended VOI (iVOI). The transition regions were on average 3.8 mm and the average full width at half maximum of the signal profile was 30 mm for an iVOI size of 30*30*30 (mm3). No displacement was observed in the signal profiles. To avoid overlapping signal profiles, the minimum separation between two iVOIs was found to be 10 mm in our magnetic resonance (MR) system. A substantial negative signal contribution from regions outside the iVOI was measured in the y-direction for 1VOI acquisition and one of the two VOIs in 2VOI acquisition. The other VOI in 2VOI acquisition exhibited only minor contamination. The measurements presented underline the importance of detailed knowledge on the volume selection performance in in vivo magnetic resonance spectroscopy.