Retention and migration of alprostadil cream applied topically to the glans meatus for erectile dysfunction.

Retention and migration of a specially designed alprostadil transdermal cream was assessed after single-dose administration to the glans meatus of the penis. Seven men were enrolled in this two-way crossover study. Three subjects self-administered the radio-labeled alprostadil transdermal cream (approximately 100 mg of cream containing 300 microg alprostadil) by inserting the tip of the dispenser into the meatus. In three others, the dose was administered by dispensing the cream dropwise into the metal opening without touching the penis (the preferred and directed method). Retention and migration of the cream mass was measured in the penis with a gamma scintillation camera. The alprostadil transdermal cream was retained in the fossa navicularis at or near 99% in five of six subjects regardless of the method of dosing, thus indicating that the cream formulation performed as designed. A mild, transient burning sensation in the penis was the most common adverse event.

The effect of hypoxia on thallium kinetics in cultured chick myocardial cells.

To assess the effect of hypoxia on cellular thallium-201 (201Tl) uptake and washout independent of coronary flow, we studied thallium kinetics during normoxia and hypoxia in cultured chick ventricular cells. Monolayers of contracting ventricular cells grown on coverslips were placed in a chamber and perfused to asymptote with media containing 201Tl. Perfusates were equilibrated with 5% CO2-95% air or 5% CO2-95% nitrogen for normoxia and hypoxia, respectively. Washout thallium kinetics were then observed during perfusion with unlabeled media. Twenty paired experiments were performed, randomly alternating the sequence of normoxia and hypoxia. Pharmacokinetics for thallium were determined by computer using standard formulae. Thallium uptake and washout were best described by assuming that intracellular thallium was contained within a single compartment. Cellular thallium uptake, as well as transfer rate constants for thallium uptake and for thallium washout during normoxia and hypoxia, were compared using paired t-tests. During normoxia and hypoxia, respectively, thallium uptake was 22 +/- 7% and 19 +/- 7% of asymptote (p less than 0.01); the compartmental rate constant for uptake by the cell was 0.16 +/- 0.07 min-1 and 0.15 +/- 0.06 min-1 (N.S.); and the transfer rate constant for washout from the cell was 0.26 +/- 0.06 min-1 and 0.23 +/- 0.05 min-1 (p less than 0.01). We conclude that there was a small (14%) decrease in thallium uptake during hypoxia. The rate of thallium uptake and washout was slightly less during hypoxia, although only the rate of washout was significantly less. These data show that cellular accumulation of thallium and the rate of washout of thallium were minimally decreased by hypoxia independent of blood flow.

Biologic gastric emptying time in diabetic patients, using Tc-99m-labeled resin-oatmeal with and without metoclopramide.

Biologic gastric emptying time (BGET) was measured in 24 patients with severe diabetes mellitus complicated by vascular damage and peripheral or sensory neuropathy. This population had a BGET of 192 +/- 32.9 min (mean +/- s.e.m. normal 40-85 min). Patients with diabetic gastroenteropathy had prolongation of BGET to 295 +/- 45 (p < 0.05). Metoclopramide significantly shortened BGET in this subgroup to 101 +/- 40 min, with return to normal values in eight of the 12 patients given the drug. The Tc-99m-labeled resin-oatmeal test meal used as described in this study provides a reliable measure of BGET and of the response to metoclopramide.

Gastrointestinal behavior of orally administered radiolabeled erythromycin pellets in man as determined by gamma scintigraphy.

The behavior of single 250-mg doses of a multiparticulate form of erythromycin base (ERYC(R)), each including five pellets radiolabeled with neutron-activated samarium-153, was observed by gamma scintigraphy in seven male subjects under fasting and nonfasting conditions. The residence time and locus of radiolabeled pellets within regions of the gastrointestinal tract were determined and were correlated with plasma concentrations of erythromycin at coincident time points. Administration of food 30 minutes postdosing reduced fasting plasma erythromycin Cmax and area under the plasma erythromycin versus time curve (AUC) values by 43% and 54%, respectively. Mean peak plasma concentration of erythromycin (Cmax) in the fasting state was 1.64 micrograms/mL versus 0.94 micrograms/mL in the nonfasting state. Total oral bioavailability, as determined by mean AUC (0-infinity) of the plasma erythromycin concentration versus time curve, was 7.6 hr/micrograms/mL in the fasted state, versus 3.5 hr/micrograms/mL in the nonfasting state. Mean time to peak plasma erythromycin concentration (tmax) in the fasting state was 3.3 hours, versus 2.3 hours in the nonfasting state. Plasma concentrations of erythromycin in both fasting and nonfasting states were within acceptable therapeutic ranges. Evidence provided by this study: 1) indicates that pellet erosion and absorption of active erythromycin base begins when the enteric-coated pellets reach the highly vascular mucosa of the jejunum and proximal ileum, and is essentially completed within the ileum, with a significant portion absorbed in the medial-to-distal ileum; 2) confirms that acceptable therapeutic plasma levels of erythromycin are attained in nonfasting subjects (Cmax = 0.94 microgram/mL) and that superior plasma erythromycin concentrations (Cmax = 1.64 micrograms/mL) are achieved by administration of the dose on an empty stomach 1 to 2 hours before or after meals; 3) corroborates other comparative studies reporting greater fasting bioavailability with this multiparticulate dosage form of erythromycin base than with reference single tablet or particle-in-tablet formulations; and 4) indicates that neutron activation of stable isotopes incorporated as a normal excipient in industrially-produced formulations provides an effective means for in vivo evaluation of dosage forms through gamma scintigraphy.

Noninvasive dissolution measurement using perturbed angular correlation.

A novel noninvasive technique was developed to measure dissolution of the water-soluble component of a solid dosage form using indium 111 and perturbed angular correlation. The method involves time-delayed coincidence counting of two cascading gamma-rays that exhibit angular correlation. This angular correlation can be perturbed if the intermediate excited state of the nucleus is reoriented due to an interaction with its environment. When such an interaction occurs, as in a phase change (solid to liquid), the perturbation changes can be shown by anisotropy. A highly perturbed condition in the solid state results in low values (0.02-0.04), while increasing values of anisotropy indicate dissolution. Anisotropy values reach 0.14-0.15 when the total unperturbed physical state (liquid) exists. The worth of this technique was demonstrated by both in vitro and in vivo determinations of dissolution rates.

Rate and pattern of gastric emptying in humans using 99mTc-labeled triethylenetetraamine-polystyrene resin.

The preparation and application of a new radiopharmaceutical used in the investigation of the rate and pattern of gastric emptying by external scintigraphy are described. Triethylenetetraamine was bound covalently to cross-linked chloromethylated polystyrene. The triethylenetetraamine-polystyrene resin tenaciously and rapidly bound technetium 99m. The gastric emptying rate was evaluated in normal adult volunteers and patients by serially recording the gastric radioactivity after ingestion of a test meal mixed with 99mTc-labeled triethylenetetraamine-polystyrene resin. The data indicated that 99mTc-labeled triethylenetetraamine-polystyrene resin was an ideal agent for assessing the rate and pattern of gastric emptying in humans. The gastric emptying half-time (t 1/2 GE) in normal subjects ranged from 25 to 75 min.

Disposition of radiolabelled suppositories in humans.

The disposition of Witepsol H 15 suppositories radiolabelled with [99mTc] technetium hydroxymethyldiphosphonate was studied after rectal administration in volunteers. The migration of the radiolabel was monitored continuously by external scintigraphy. The resulting scintiphotos were superimposed on lower GI radiographs to determine the extent of spreading of the dosage form in the rectum. The dosage form migrated approximately 5-7 cm into the rectum in nearly all of the studies and was, in general, confined to the lower and middle regions of the rectum. Since the venous supply to the lower rectum leads primarily to the inferior vena cava, the data presented here indicate that the metabolism of drugs sensitive to the 'first-pass' effect may be partially avoided by their rectal administration.

Purposeful alteration of [99mTc]-pertechnetate biodistribution.

A series of imaging studies were conducted in rats to assess the effect of stannous containing chemical species on the normal biodistribution of [99mTc]pertechnetate. The goal of the study was to determine if tissue activity could be altered by use of selected chemical agents and if such alteration could be used to clear non-target activity for enhanced image interpretation and/or to visualize two or more organ systems following a single injection of radioactivity. Two distinct patterns of tissue activity alteration could be induced. Tissue distribution studies in rats demonstrated statistically significant differences between tissue radioactivity in groups selectively studied for the type and magnitude of the induced alteration.

An in vitro/in vivo correlation for the disintegration and onset of drug release from enteric-coated pellets.

An empirical mass-transfer model for enteric-coating dissolution that uses in vivo dissolution data to characterize the pH-dependent solubility properties of the polymer film and a mass-transfer coefficient determined from in vivo dissolution or disintegration studies is developed. Once the in vivo mass-transfer coefficient has been evaluated, it can be used in conjunction with in vitro dissolution data from other formulations to predict the in vivo time to disintegration and onset of drug release. Results of in vitro dissolution experiments using the USP basket dissolution apparatus and in vivo disintegration experiments using gamma scintigraphy with four enteric-coated pellet formulations are presented. The good agreement among the in vivo mass-transfer coefficients that were determined supports the validity of the model.

Detection of upper abdominal abscesses by radionuclide imaging.

An improved means of detecting upper abdominal abscesses using the dual radionuclide subtraction technique was applied to 51 patients. 67Gallium citrate was used in the localization of the lesion and 99Tc-labeled human albumin microspheres and 99Tc sulfur colloid were used for subtracting out the interfering background from normal organ concentrations. The procedure provided the parameter capabilities for localization of the abscesses as well as information on their shape and size. Compared to nonsubtraction Ga procedures, 53% more abscesses were diagnosed using the subtraction technique.

Dual-isotope imaging of neutron-activated erbium-171 and samarium-153 and the in vivo evaluation of a dual-labeled bilayer tablet by gamma scintigraphy.

The feasibility of dual-label scintigraphic studies which use the neutron-activated isotopes erbium-171 and samarium-153 is described. Experimental details are provided to correct and minimize the compton scatter contribution of 171Er into the lower-energy 153Sm window. The results from this study demonstrate that this dual-label procedure is sensitive enough to monitor simultaneously the behavior of two discrete regions of the same unit dose in the gastrointestinal tract of man.

Correlation of ibuprofen bioavailability with gastrointestinal transit by scintigraphic monitoring of 171Er-labeled sustained-release tablets.

External gamma scintigraphy was used to monitor the gastrointestinal (GI) transit of radiolabeled sustained-release tablets containing 800 mg ibuprofen in eight fasted healthy volunteers. Ibuprofen serum concentrations were determined from blood samples drawn sequentially over a 24-hr period. Serum concentrations and related parameters were correlated to the position of the dosage form in the GI tract from the scintiphotos. The sustained-release tablets were radiolabeled intact utilizing a neutron activation procedure, by incorporating 0.18% of 170Er2O3 (enriched to greater than 96% 170Er) into the bulk formulation. After manufacture of the final dosage forms, the tablets were irradiated in a neutron flux (4.4 x 10(13) n/cm2.sec) for 2 min, converting the stable 170Er to radioactive 171Er (t1/2 = 7.5 hr). Each tablet contained 50 microCi of 171Er at the time of administration. The scintigraphy studies suggested that the greatest proportion of ibuprofen was absorbed from this dosage form while the tablet was in the large bowel. The dosage forms eroded slowly in the small bowel and appeared to lose their integrity in the large bowel. In vitro studies showed only minimal effects of the neutron irradiation procedure on the dosage form performance.

Cholescintigraphy in the detection of cholelithiasis: a review of 23 cases and a case report demonstrating the sequential evolution of the appearance of the gallbladder defect.

Cholescintigraphy of cholelithiasis has been reported as a defect or photon deficient area in the gallbladder. We present the case of a patient with gallstones whose cholescintigraphic study showed a sequential evaluation of the scan appearance from a defect, to a septation, a hole, and finally a filled-in appearance. Cholescintigrams and histopathologic findings after cholecystectomy of another 22 patients with cholelithiasis were also retrospectively reviewed. The results of the study concluded that: cholelithiasis is rarely demonstrated by cholescintigraphy and nonvisualization of the gallbladder may be due to acute or chronic cholecystitis associated with cholelithiasis.

The use of the 99mTc-pertechnetate neck/thigh ratio as a test of thyroid function.

A total of 100 patients were studied by standard thyroid function tests and the 99mTc-pertechnetate neck/thigh ratio was determined. This ratio or "trapping index" correlated closely with 131I uptake. The 99mTc test should be followed by scanning at 20 minutes to distinguish diffuse from localized thyroid disease. TSH stimulation and suppression studies can be done. It is recommended that this ratio be used in place of the standard 24-hour RAIU study, as it gives the same information at a saving in time, money, and radiation exposure.

The effect of food on gastrointestinal (GI) transit of sustained-release ibuprofen tablets as evaluated by gamma scintigraphy.

The GI transit of radiolabeled sustained-release ibuprofen 800-mg tablets in eight healthy, fed volunteers was monitored using external gamma scintigraphy. Ibuprofen serum concentrations were determined from blood samples drawn over 36 hr following dosing. Sustained-release ibuprofen tablets containing 0.18% of 170Er2O3 (greater than 96% 170Er) in the bulk formulation were manufactured under pilot-scale conditions and were radiolabeled utilizing a neutron activation procedure which converted stable 170Er to radioactive 171Er (t1/2 = 7.5 hr). At the time of dosing, each tablet contained 50 mu Ci of 171Er. Dosage form position were reported at various time intervals. In five subjects the sustained-release tablet remained in the stomach and eroded slowly over 7-12 hr, resulting in gradual increases in small bowel radioactivity. In the remaining three subjects, the intact tablet was ejected from the stomach and a gastric residence time of approximately 4 hr was measured. This is in marked contrast to a previous study conducted in fasted volunteers in which gastric retention time ranged from 10 to 60 min. Differences in GI transit between fed and fasted volunteers had little effect on ibuprofen bioavailability. AUC and Tmax were unaltered and Cmax was increased by 24%, which is in agreement with results from a previous, crossover-design food effect study.

In utero fetal lamb thyroidectomy and thyroid autograft transplantation.

Our fetal surgical model was utilized to perform in utero fetal lamb thyroidectomy and autograft transplantation of thyroid tissue to fetal thigh at 82-93 days gestation. Successful in utero transplantation was possible in two of six experimental animals. In one twin pregnancy with an unoperated control lamb, observations were continued to age six months. The athyrotic lamb with a thigh autograft was larger at birth and had a transient weak sucking reflex and awkward gait. It then grew and developed normally with no stigmata of cretinism or delay in bone maturation. At age six months an increase in thyroid stimulating hormone (oTSH) was the single distinguishing observation in the twin with the transplant. Although oTSH levels were elevated to age six months, the pituitary continued to be responsive to thyrotropin releasing hormone (TRH) stimulation. These findings suggest that in utero transplantation of thyroid tissue is technically feasible and that the previously described development of in utero cretinism following fetal thyroidectomy can be prevented by a functioning autograft. This technique will be useful in attempting allograft transplantation in utero.