Development of an IHE MRRT-compliant open-source web-based reporting platform.

OBJECTIVES: To develop a platform that uses structured reporting templates according to the IHE Management of Radiology Report Templates (MRRT) profile, and to implement this platform into clinical routine. METHODS: The reporting platform uses standard web technologies (HTML / JavaScript and PHP / MySQL) only. Several freely available external libraries were used to simplify the programming. The platform runs on a standard web server, connects with the radiology information system (RIS) and PACS, and is easily accessible via a standard web browser. RESULTS: A prototype platform that allows structured reporting to be easily incorporated into the clinical routine was developed and successfully tested. To date, 797 reports were generated using IHE MRRT-compliant templates (many of them downloaded from the RSNA's radreport.org website). Reports are stored in a MySQL database and are easily accessible for further analyses. CONCLUSION: Development of an IHE MRRT-compliant platform for structured reporting is feasible using only standard web technologies. All source code will be made available upon request under a free license, and the participation of other institutions in further development is welcome. KEY POINTS: • A platform for structured reporting using IHE MRRT-compliant templates is presented. • Incorporating structured reporting into clinical routine is feasible. • Full source code will be provided upon request under a free license.

Evaluation of mucosal damage of surfactants in rat jejunum and colon.

Surfactants are one of the most frequently used adjuvants in oral pharmaceutical preparations, used primarily as solubilizers, stabilizers, emulsifiers, and wetting agents. However, surfactants can disrupt normal membrane structure. In this study, lactate dehydrogenase (LDH) and mucus were evaluated as potential markers of intestinal damage in a single-pass in situ perfusion model in the rat. The release of LDH and mucus into the intestinal lumen of the rat following perfusion of the nonionic surfactants Tween 80 and Triton X-100 was determined. The release rate of LDH increased in the order saline < Tween 80 < Triton X-100 in both jejunum and colon. LDH release rate was approximately three times lower in the colon than in the jejunum, but relative effects of nonionic surfactants were comparable between regions. In addition, the rate of LDH release in the jejunum increased with decreasing perfusion rates for both saline and Tween groups and with increasing Tween 80 concentrations. At each flow rate studied, mucus release rate was greater in the presence of Tween 80 and Triton X-100 than saline, but there was no significant difference between the effect of Tween 80 and Triton X-100 on mucus release rate. When perfusion of Triton X-100 was followed by saline, rates of both mucus and LDH release returned to baseline values, suggesting damage is reversible. Histological damage agreed with trends observed in LDH and mucus release rates. This model allows for early evaluation of intestinal damage due to both excipients and active ingredients and simultaneous measurement of drug absorption.

Optimizing Caco-2 cell monolayers to increase throughput in drug intestinal absorption analysis.

INTRODUCTION: The aim of this investigation was to evaluate methods for increasing Caco-2 cell throughput for assessing drug intestinal absorption. The use of 6-, 12-, and 24-well membranes and the effect of membrane size on permeability and the integrity of the Caco-2 cell monolayer were assessed. In an effort to optimize the assessment of drug permeability, increased throughput was investigated by testing compounds singly or as mixtures of analytes. METHOD: The transepithelial electrical resistance (TEER) of cell monolayers was measured on 0.33, 1.0, and 4.7 cm2 polycarbonate membranes using EVOM, over a 25-day period. Absorptive transport was determined on all compounds tested using LC-MS/MS assays, or liquid scintillation spectrometry. RESULTS: The effect of multiple compounds in one well compared to single compounds was assessed with atenolol, nadolol, metoprolol, and propranolol for mixtures of four compounds and with RWJ-53308, atenolol, terbutaline, propranolol, naproxen, piroxicam, topiramate, and furosemide for mixtures of eight compounds. The apparent permeability (Papp) values correlated well between single analytes and mixtures of four and eight analytes in each well. Drug permeability decreased slightly with an increase in well size. The TEER value increased with the number of days in culture for each of the 6-, 12-, and 24-well sizes. DISCUSSION: It was demonstrated that the 24-well format system is ideal for high-throughput assessment. Furthermore, the approach of mixing four or eight analytes in each well to further increase throughput was also demonstrated to be valid.

Application of a radiotelemetric system to evaluate the performance of enteric coated and plain aspirin tablets.

The bioavailability of enteric coated and plain aspirin tablets was studied in four beagle dogs. Blood sampling for enteric coated tablets was planned with the aid of a radiotelemetric system. The release of aspirin from its dosage form was detected by monitoring the change in intestinal pH. Aspirin and salicylic acid levels in plasma obtained from the enteric coated dosage form exhibited familiar concentration versus time absorption profiles. Variation in the plasma concentrations of these two compounds within each dog studied (four runs each) was relatively small when time zero was adjusted to the commencement of tablet dissolution. The plasma levels obtained from plain aspirin (three runs each), however, show atypical absorption. The estimated absolute bioavailability was 0.432 +/- 0.0213 and 0.527 +/- 0.0260 for enteric coated and plain aspirin, respectively. Other pharmacokinetic parameters for these two dosage forms such as the highest observed plasma concentration (Cmax) (10.9 +/- 0.535 microgram/mL versus 13.6 +/- 1.88 micrograms/mL) and the time to reach Cmax (tmax) (26.6 +/- 1.94 min versus 31.0 +/- 7.04 min) agree well. The mean values for gastric emptying time, in vivo coating dissolution time, and in vivo disintegration/dissolution time of the tablet core for enteric coated aspirin are 48.7 +/- 7.23 min, 44.3 +/- 3.80 min, and 34.7 +/- 2.04 min, respectively.

Absorption of ACE inhibitors from small intestine and colon.

The intestinal absorption of two ACE inhibitors was studied to determine the potential for colonic delivery of small peptides. In addition, studies were also performed to assess intestinal tissue uptake and evaluate a canine intestinal-access-port model as techniques for screening absorption. To evaluate the impact of differences in the contributions of passive permeation and carrier-mediated peptide transport on in vitro uptake and in vivo absorption, an esterified prodrug, benazepril, and a free diacid non-prodrug, CGS 16617, were selected for study. Potential colonic absorption enhancement utilizing coadministration of Intralipid was also investigated. Studies in rat everted intestinal rings verified that jejunal benazepril uptake included a carrier-mediated component while that of the diacid did not. Uptake of both drugs was purely passive in colonic rings. Equilibrium uptake and uptake rate of the more lipophilic prodrug was 2-fold greater than the diacid. Benazepril and CGS 16617 jejunal uptake rate at 0.01 mM was 3.5 and 2.5 times higher, respectively, than from colonic rings. Following jejunal administration in dogs, maximum benazepril plasma levels (Cmax) and area under the plasma level versus time curve (AUC) were 5.5 and 3.0 times higher, respectively, than following colonic administration. Maximum benazepril plasma levels following colonic administration in dogs was 2-fold greater than for CGS 16617, consistent with in vitro results. Colonic coadministration of the poorly-absorbed CGS 16617 with 2 mL of Intralipid (within dietary range for fecal fat content) enhanced Cmax and AUC 2.5- and 3.5-fold, respectively, in the dog and AUC 1.5-fold in the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

The medical engineering program of Forschungszentrum Karlsruhe.

The research activities of the Forschungszentrum Karlsruhe on minimally-invasive surgery (MIS) have for several years improved techniques and instrumentation for different types of MIS. Many types of instruments and robotic devices have been developed and new techniques implemented. In this paper we present the most recent results from our different projects, such as endoscopic heart surgery, tracking systems, a camera guidance device, telemanipulator systems, minimally-invasive breast biopsy in closed-bore MRI, endoscopic training simulators and developments using smart materials (e.g. Nitinol).

The influence of variable gastric emptying and intestinal transit rates on the plasma level curve of cimetidine; an explanation for the double peak phenomenon.

A physiological flow model is presented to account for plasma level double peaks based on cyclical gastric emptying and intestinal motility in the fasted state. Central to the model is the assumption that gastric emptying and intestinal transit rates will vary directly with the strength of the contractile activity characteristic of the fasted state motility cycle. Simulated curves clearly indicate that variable gastric emptying rates can result in variable absorption rates from the gastrointestinal tract and double peaks in the plasma level curves of cimetidine. Vital to the occurrence of double peaks are (i) dosing time relative to phasic activity, (ii) variability in flow out of the stomach, and (iii) a small emptying rate constant Qs/Vs, for a period of time within the first hour after administration. Variability in intestinal flow rates alone does not cause a double peak in the plasma level curve. Results of the simulations, as well as experimental results, can be categorized according to the shapes of the plasma level curves into four types: type A, Cpmax (1) less than Cpmax (2); type B, single peak; type C, Cpmax (1) greater than Cpmax (2); type D, Cpmax(1) = Cpmax(2). Assuming that the experimental results were obtained from fasted subjects, with the time of dose administration being a random variable, the frequency of the experimental curves having shape A, B, C, or D correlates extremely well with theoretical predictions. It is concluded that variable gastric emptying rates due to the motility cycle can account for plasma level double peaks. Furthermore, variable gastric emptying rates combined with the short plasma elimination half-life and poor gastric absorption of cimetidine can be the cause of the frequently observed plasma level double peaks.

Pharmacokinetics and metabolism of diclofenac sodium in Yucatan miniature pigs.

The pig has been suggested as an animal model in biomedical research because of its physiological similarity to man. Therefore, the pharmacokinetics and metabolism of diclofenac sodium (Voltaren) were studied in four Yucatan minipigs after intravenous administration of 25 and 50 mg and oral administration of 50 mg in a solution of 50 mL buffer, 50 mL water, and 200 mL water, and the results compared to historical data in man. The absolute bioavailability after oral administration of 50 mL buffer, 50 mL water, and 200 mL water solutions were 107, 97, and 109%, respectively, compared to approximately 50% in man. The total plasma clearance in minipigs was fivefold slower than in humans (57 +/- 17 vs 252 +/- 54 mL/hr/kg). The plasma levels of the metabolites 4'-hydroxy, 5-hydroxy, 3'-hydroxy, 4',5-dihydroxy, and 3'-hydroxy-4'-methoxy diclofenac were considerably lower in minipigs than in man after both i.v. and oral administration. These results suggest slower metabolism and/or enterohepatic recirculation of the parent drug in minipigs. The volume of distribution of the central compartment was 40% less in humans than in pigs (39 vs 67 mL/kg). The terminal half-lives of the parent drug were similar in pigs (2.4 hr) and humans (1.8 hr). The rate of oral drug absorption increased in the order of 50 mL aqueous, 200 mL aqueous, and 50 mL buffered solutions (Ka = 0.52 +/- 0.11, 0.59 +/- 0.13, and 1.2 +/- 0.7 hr-1, respectively). These trends are similar in man and suggest that both buffering and intake volume can affect diclofenac absorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral absorption of CGS-20625, an insoluble drug, in dogs and man.

Oral bioavailability of highly water-insoluble drugs is often quite limited and variable, requiring the development of improved formulations. Animal models are an essential aspect of the design and testing of such formulations designed to improve absorption in man. The present report compares the absorption of CGS-20625, an insoluble drug, in dog and man after oral administration of the drug as a powder, a solid dispersion capsule, and after gastric and duodenal administration in PEG 400 solution. CGS-20625 powder (20 mg) given orally exhibited slow, delayed absorption in both dog and man, with a Cmax of 0.26 +/- 0.07 microgram/ml at Tmax of 3 hr in dog, and 0.01 +/- 0.004 microgram/ml at 2 hr in man. Administration of CGS-20625 in PEG 400 solution improved absorption in dog and man, with a Cmax of 1.2 +/- 0.10 microgram/ml at Tmax of 0.25 hr in dog, and a Cmax of 0.10 +/- 0.04 microgram/ml at 0.5 hr in man. Tmax after administration of the hard gelatin capsule formulation was 0.9 and 1.0 hr in dog and man, with Cmax of 0.89 +/- 0.16 and 0.052 +/- 0.014 microgram/ml, respectively. Absolute bioavailability of CGS-20625 powder in the dog was 0.67 +/- 0.21, whereas the bioavailabilities of the powder and the capsule relative to the PEG 400 solution were 0.84 and 1.1, respectively, in dog, and 0.41 and 0.85 respectively, in man. No significant benefits of duodenal administration were observed. Plasma levels were approximately 10-fold greater and oral clearance was approximately 5-fold less in the dog than in man. Furthermore, pharmacokinetic data were less variable and relative bioavailability was greater in dogs than in humans. Physiological factors in the gastrointestinal tract or greater first-pass metabolism in man may account for these species differences. The relative rate and extent of CGS-20625 absorption were similar between dog and man, in the order of powder < capsule < PEG 400 solution. In addition, in vivo absorption rates in both species reflect in vitro dissolution differences between the powder and the capsule. These data strongly support the use of the dog as a model for developing improved formulations of CGS-20625. Further investigation of the dog as a model to evaluate insoluble drug absorption is warranted.

In vitro and in situ permeability of a 'second generation' hydroxypyridinone oral iron chelator: correlation with physico-chemical properties and oral activity.

PURPOSE: The in vitro and in situ transport of CGP 65015 ((+)-3-hydroxy-1-(2-hydroxyethyl)-2-hydroxyphenyl-methyl-1H-pyridin-4-on e), a novel oral iron chelator, is described. The predictive power of these data in assessing intestinal absorption in man is described. METHODS: Caco-2 epithelial monolayer and in situ rat jejunum perfusion intestinal permeability models were utilized. In vivo iron excretion and preliminary animal pharmacokinetic experiments were described. Ionization constants and octanol/aqueous partition coefficients were measured potentiometrically. Solubilities and intrinsic dissolution rates were determined using standard procedures. RESULTS: Caco-2 cell (Papp approximately 0.25 x 10(-6) cm x s(-1)) and rat jejunum (Pw approximately 0.4) permeabilities of CGP 65015 were determined. The log D(pH 7.4) of CGP 65015 was 0.58 and its aqueous solubility was < 0.5 mg x ml(-1) (pH 3-9). The intrinsic dissolution rate of CGP 65015 in USP simulated intestinal fluid was 0.012 mg x min(-1) x cm(-2). CGP 65015 promotes iron excretion effectively and dose dependently in animals. CONCLUSIONS: Caco-2 and rat intestinal permeabilities predict incomplete oral absorption of CGP 65015 in man. Preliminary rat pharmacokinetics support this. Physico-chemical data are, also, in line and suggest that CGP 65015 may, in addition, be solubility/dissolution rate limited in vivo. Nevertheless, early animal pharmacological data demonstrate that CGP 65015 is a viable oral iron chelator candidate.

The influence of the interdigestive migrating myoelectric complex on the gastric emptying of liquids.

It is unknown how the interdigestive migrating motor complex influences the gastric emptying of liquids. Therefore, the gastric emptying rate of 50- and 200-mL volumes of phenol red solution were measured while monitoring contractile activity. Motor activity was recorded using a hydraulic manometric system and expressed as either the proximity of dosing time to time of appearance of phase III or as a motility index, defined as (contractile area)/(sampling interval time). After an initial lag period, emptying was log linear. With a 50-mL oral dose, the mean gastric emptying rate of the log-linear phase was successively faster during phase I (0.018 +/- 0.003 min-1), phase II (0.083 +/- 0.031 min-1), and late phase II/III (0.171 +/- 0.066 min-1) (P less than 0.05). Similarly, the mean lag time decreased successively with phases I, II, and late II/III (19.1 +/- 12.4, 7.6 +/- 5.6, and 3.8 +/- 2.8 minutes, respectively). At a 200-mL oral dose, there was no difference in the emptying rate between phase I and phase II (0.104 +/- 0.0014 vs. 0.110 +/- 0.041 min-1), but the emptying rate during late phase II/III was significantly greater (0.236 +/- 0.069 min-1); lag time was not dependent on phase. There was a statistical difference in the overall mean emptying rate between the 50- and 200-mL volumes. Also, during phase I, the emptying rate was faster for the 200-mL volume. This study shows a strong dependence of liquid gastric emptying rate and lag time on interdigestive antral motility, the emptying of small volumes being more dependent on motility phase than that of large volumes. Phase-related fluctuations in contractile activity can account for much of the reported variability in gastric emptying data. Furthermore, this study suggests that dose volume and interdigestive motor activity at the time of drug administration can affect absorption and onset of therapeutic response for some drugs.