Gastrointestinal transit of Sinemet CR in healthy volunteers.

The gastrointestinal transit and systemic absorption of Sinemet CR (50/200) and standard Sinemet (25/100) have been studied in fasting and "fed" healthy human subjects. Both formulations were labeled with a gamma-emitting radionuclide, and their gastric emptying, colon arrival, and in vivo dissolution profiles were monitored using gamma scintigraphy. The standard dosage forms were found to disperse soon after administration and to empty rapidly from both the fasting and the "fed" stomach. The erosion of the controlled-release (CR) system was independent of food. Dosing after a light breakfast altered the gastric emptying profile of the CR formulation and led to significant differences in the plasma levels of levodopa.

Circulation clearance rate of radioiodine during fibrinogen uptake tests.

Scintillation counts, following administration of 125I-labeled fibrinogen, were performed on the legs of medical and surgical patients. As part of the test procedure, precordial count rates were recorded and used in calculating the fibrinogen clearance rates. A short half-time for the circulating radioiodine was found to correlate well with the detection of venous thrombosis.

Sustained release drug delivery to the lungs: an option for the future.

There are potential therapeutic advantages in administering drugs as sustained release formulations to the lungs. This presents the challenges of controlling drug release from particles within the lung environment while overcoming the natural clearance mechanisms. Approaches being adopted involve the administration of particles of small aerodynamic diameter to the alveoli and avoiding phagocytosis by high phospholipid content or large geometric particle size. Studies in animals have demonstrated the utility of such formulations.

Evaluation of an enteric-coated delayed-release 5-aminosalicylic acid tablet in patients with inflammatory bowel disease.

Gastrointestinal transit of an enteric coated delayed release 5-aminosalicylic acid tablet radiolabelled with 111indium has been monitored in a total of 13 patients with Crohn's disease and ulcerative colitis. More than 70% of the tablets disintegrated in the small intestine, on average 3.2 hours after emptying from the stomach. Dispersed preparation was detected in the proximal colon of all the patients, except one with an ileostomy. Mean peak plasma concentrations of 5-aminosalicylic acid and its metabolite acetyl-5-aminosalicylic acid occurred 3-4 hours after gastric emptying. The tablets provide a reliable means of drug delivery to the ileum and proximal colon.

Gastrointestinal transit of an enteric-coated delayed-release 5-aminosalicylic acid tablet.

Gastrointestinal transit of an enteric-coated, delayed-release 5-aminosalicylic acid tablet radiolabelled with indium-111 has been monitored in a preliminary study with eight healthy subjects using gamma scintigraphy. Gastric emptying of the tablet was delayed by the presence of food in the stomach. Disintegration occurred about 5 hours after the tablet left the stomach. There was close agreement between the tablet disintegration times and the initial detection of drug in the blood. The site of disintegration could be established in most instances; approximately 80% of the doses resulted in drug dispersion within the ascending colon. The coated tablets provide an effective means of drug delivery to the proximal colon.

Evaluation of an enteric-coated naproxen pellet formulation.

An enteric-coated, pellet formulation of naproxen has been evaluated in eight healthy subjects. Each volunteer was dosed with 153Sm-labelled, enteric-coated pellets on two occasions, once whilst fasted and once after breakfast. Gastrointestinal transit was followed using gamma scintigraphy and drug absorption compared with that from uncoated naproxen pellets dosed on a separate occasion. The pH in the stomach and intestines was monitored using radiotelemetry capsules. Gastric emptying was delayed by dosing after breakfast, but small intestinal transit of the enteric-coated formulation was the same on both occasions. The highest pH recorded from the stomach was 4.0 and in all subjects the pH rose to at least 7.3 in the small intestine. The onset of drug absorption was fastest from the uncoated formulation and slowest from the coated pellets taken after breakfast. The total amount of drug absorbed was the same on all three occasions.

Localization of drug release sites from an oral sustained-release formulation of 5-ASA (Pentasa) in the gastrointestinal tract using gamma scintigraphy.

Release of 5-ASA from a sustained release formulation (Pentasa, Ferring A/S, Copenhagen, Denmark) was monitored with plasma sampling for up to 24 hours in nine volunteers under both fasted and fed conditions. Drug absorption was correlated with location of the sustained-release microgranules in the gastrointestinal tract by gamma scintigraphy. Disintegration of the labeled tablet preparation occurred in the stomach within 20 minutes and acetylated 5-ASA was detectable in the plasma less than 60 minutes after ingestion. No significant differences were detected in either transit times through the small intestine, peak plasma acetylated 5-ASA concentration or lag time to absorption between fasted and fed individuals. Peak plasma concentration of acetylated 5-ASA usually occurred when the microgranules were present in the small intestine or ascending colon. The pharmacoscintigraphic study confirmed that 5-ASA release from the formulation occurred throughout the gastrointestinal tract, and that food effects on the in vivo behavior of the preparation were minimal.

Lung vascular permeability in patients with acute pancreatitis.

Acute pancreatitis may be complicated by acute lung injury associated with increased lung vascular permeability to plasma protein. The pulmonary accumulation of the plasma protein transferrin, radiolabelled in vivo with indium-113m, was monitored using a portable probe radiation detector in sixteen patients with acute pancreatitis. Plasma protein accumulation (PPA) indices were within normal limits (less than 0.5 X 10(-3)min-1) in all survivors (n = 10) and elevated in all but one of the non-survivors. All non-survivors had severe acute pancreatitis as judged by standard criteria. Thus increased lung vascular permeability was not a constant feature of uncomplicated acute pancreatitis and was only observed in patients with multisystem failure accompanied by clinically evident acute lung injury.

Evaluation of 153Sm-diethylenetriaminepentaacetic acid for radiolabelling of pharmaceutical dosage forms by neutron activation.

153Sm-DTPA provides a suitable alternative to 99mTc-DTPA and 111In-DTPA as a water soluble tracer for the evaluation of pharmaceutical preparations. The chelate was handled biologically in a similar way to 99mTc-DTPA and 111In-DTPA. The chelate can be incorporated into the formulation as a non-radioactive excipient and the intact dosage form can then be neutron activated to produce 153Sm.

Lung deposition from four nebulizers.

The total and regional deposition of aerosol has been compared using four nebulizers; the Pari Boy 37.80, Pari IS-2, RespirGard II and Penta-Sonic. The aerosol was radiolabelled with [99Tcm]DTPA, administered to ten healthy subjects and the distributions monitored by gamma scintigraphy. Median lung aerosol depositions expressed as percentages of the doses initially loaded into the nebulizers were: Pari IS-2 19%, Pari Boy 37.80 13%, RespirGard II 9% and Penta-Sonic 2%. The ratios of the peripheral to central lung deposition, however, were greater with the RespirGard II and Penta-Sonic nebulizers. The choice of the most appropriate nebulizer depends on the pharmaceutical being administered, since aerosol must be delivered to the required site in sufficient quantity, whilst minimizing the incidence of local or systemic side-effects.

Characterisation of the in vivo behaviour of a controlled-release formulation of levodopa (Sinemet CR).

The gastrointestinal transit and systemic absorption of Sinemet CR (50-200) controlled-release tablets and standard Sinemet (25-100) immediate-release (IR) tablets have been studied in fasted and fed healthy human subjects. Both formulations were labelled with a gamma-emitting radionuclide and their gastric emptying, colon arrival and in vivo disintegration profiles monitored using gamma scintigraphy. The IR dosage forms were found to disperse soon after administration and to empty rapidly from both fasted and fed stomachs. Erosion of the CR system was independent of food or stomach pH. The CR tablet was observed to disintegrate fully in the gastrointestinal (GI) tract, resulting in complete release of levodopa over a 3-4 h time period. Considerable intersubject variation was found to exist for levodopa absorption. Absorption was more protracted with Sinemet CR than with standard Sinemet, due to the controlled release characteristics of the tablet matrix. There was no rapid initial absorption phase and instead, a gradual build-up in the absorption profile occurred.

An index for monitoring bone metastases from carcinoma of the prostate.

The bone uptake of 99Tcm-methylene diphosphonate has been monitored quantitatively in patients undergoing treatment for carcinoma of the prostate. The uptake is expressed as a function of the administered dose. The results show that oestrogen therapy has no significant effect on the uptake into normal bone. Case reports are presented illustrating the use of the technique.

The investigation of neonatal obstructive jaundice using 123I rose bengal.

With the development of new surgical techniques the outlook for infants with biliary atresia has improved significantly. It has therefore become increasingly important to identify these patients quickly in order to allow prompt surgical intervention. Differentiation of biliary atresia from other causes of jaundice, in particular idiopathic neonatal hepatitis, is often difficult as there is considerable clinical and histological overlap of the two conditions. Demonstration of biliary patency using radiopharmaceuticals is a well established technique. 131I rose bengal and the 99Tcm-labelled iminodiacetic acid derivatives have both been used, but are not completely satisfactory, and controversy still exists as to which is the most suitable agent. Nine infants with prolonged jaundice have been studied using 123I-labelled rose bengal. All infants with biliary atresia and neonatal hepatitis were correctly identified. The results indicate that 123I rose bengal provides a reliable tracer for assessing biliary patency and is the agent of choice in the investigation of neonatal obstructive jaundice.

A comparison between magnetic resonance imaging and scintigraphic bone imaging in the diagnosis of disc space infection in an animal model.

In a controlled prospective study, 33 rabbits were used to compare the efficacy of magnetic resonance imaging (MRI) to scintigraphy in diagnosing pyogenic infection of the intervertebral disc. A suitable inoculum of Staphylococcus aureus (10(8) organisms) was injected into a test level while a similar volume of sterile culture medium was injected into a control disc in each animal. Plain radiographs, MRI, and scintigraphic bone images then were performed at regular intervals after operation. The imaging studies were interpreted blind, as was the final histologic assessment. Five animals died of respiratory complications following sedation. In the remaining 28 animals, 23 developed infection at the test level, and four developed infection at the control disc. Magnetic resonance imaging was found to be more sensitive than scintigraphy in diagnosing discitis, particularly in the early stages of the disease. The overall results showed MRI had a sensitivity of 93%, specificity of 97%, and accuracy of 95%. There were two false-negative results and one false-positive. In contrast, scintigraphy had a sensitivity of 41%, specificity of 93%, and accuracy of 68%. There were two false-positive and 16 false-negative results. Plain radiographs had a sensitivity of 82%, specificity of 93%, and accuracy of 88%. There were two false-positive and five false-negative results. The MRI appearance of discitis was characteristic from an early stage in the disease, and preceded the changes on scintigraphy and plain radiographs by several days in the majority of cases.

Administration of an insulin powder to the lungs of cynomolgus monkeys using a Penn Century insufflator.

A powder formulation of live-attenuated measles vaccine is being developed for administration to the lungs. The safety and efficacy of the powder will be assessed by insufflation into cynomolgus monkeys. A Penn Century insufflator has been evaluated for powder dosing to the monkeys using an insulin formulation having similar physicochemical characteristics to the vaccine powder. Insulin pharmacokinetics were compared following dosing by powder insufflation, solution instillation into the trachea and subcutaneous injection. The insulin dosed to the lungs and trachea was more rapidly absorbed than that administered subcutaneously. Insulin bioavailability was greater from the inhaled powder than from the instilled solution. The findings confirm that the Penn Century device is suitable for vaccine powder dosing to the deep lung.

Validity of the geometric mean correction in the quantification of whole bowel transit.

The accurate interpretation of gastrointestinal transit studies often requires quantification of the data. Particles radiolabelled with indium-111 have been monitored using a gamma camera, during transit through the stomach and the small and large intestines of normal subjects. The count rates measured from either anterior or posterior images alone showed considerable variations, and depended on the site of the tracer within the gut. The geometric mean values of corresponding anterior and posterior count rates remained almost constant throughout each study.

Intra-operative nuclear medicine in surgical practice.

The use of radionuclides for the intra-operative localization of tumours has increased steadily over the past 15 years. We reviewed more than 15 years experience of a peripatetic service using a sterilizable probe system in operating theatres throughout the UK for localizing bone and soft tissue lesions. The technique requires the positive concentration of an appropriate radiopharmaceutical, together with a suitably designed detector system which can be sterilized for use during surgery. All surgical procedures were undertaken following initial positive imaging studies. A well-collimated nuclear probe with a 5 mm diameter CdTe detector was sterilized with ethylene oxide gas and coupled to a digital counter and ratemeter for use in the operating theatre. A total of 68 surgical procedures have been undertaken at 35 hospitals. Fifty-eight patients underwent excision of osteoid osteoma subsequently proven by histology. The other lesions successfully resected included osteoblastoma, hamartoma, Brodie's abscess, chronic bone infection, ectopic parathyroid adenoma and metastatic neuroblastoma. The technique can now be regarded as the method of choice for the surgical localization of osteoid osteoma. The successful detection of lesions at surgery can be assured providing that clear localization of the radiopharmaceutical occurs on the pre-operative images. The intra-operative use of conventional and new tumour-specific radiopharmaceuticals is reviewed and we confirm an increasing role for the surgical-probe-guided localization of primary and metastatic tumours.

Exercise and small intestinal transit.

The transit of 99Tcm-labelled particles through the small intestine has been monitored in nine healthy subjects undergoing three levels of exercise. The mean +/- 1S.D. small intestine transit times under conditions of minimal, moderate and strenuous activity were 4.5 +/- 1.7 h, 5.4 +/- 2.5 h and 4.1 +/- 1.8 h, respectively. These findings indicate that the bioavailability of drugs from controlled release preparations passing through the small intestine is unlikely to be affected by variations in normal daily activity.

An improved technique of intra-operative bone scanning.

Radiopharmaceuticals have been successfully used to detect occult neoplasms and infective lesions. Bone scans using 99mTc-labelled methylene diphosphonate located osteoid osteomas accurately in a series of 30 symptomatic patients. A portable radiation detector system has been designed to help intra-operative localisation and facilitate complete excision of the lesions with minimal damage to normal tissue. A sodium iodide detector with a fibre-optic link was used at first, but a cadmium telluride system has provided a more durable, reliable and sensitive sterilisable probe.

The effect of eating on transit through the small intestine.

The effect of eating on the transit of radiolabelled particles through the small intestine has been monitored in eight healthy subjects dosed after an overnight fast. Each subject participated on three occasions and either remained fasting for 9 h after dosing or consumed a meal at 1.5 h or 4 h. The mean +/- 1 S.D. small intestinal transit time during the fasting study was 5.5 +/- 2.1 h and during the 1.5h and 4 h fed studies 4.8 +/- 2.9 h and 4.7 +/- 2.2 h, respectively. These times were not significantly different, nor were the rates of entry of the particles into the colon. These findings indicate that once in the small intestine the efficacy of orally administered pharmaceutical preparations is unlikely to be affected by eating.