External Gamma Counting Research Articles

Long-Term Clearance Kinetics of Inhaled Ultrafine Insoluble Iridium Particles from the Rat Lung, Including Transient Translocation into Secondary Organs

Recently it was speculated that ultrafine particles (UFP) may translocate from deposition sites in the lungs to systemic circulation and whether long-term clearance differs between ultrafine and micrometer-sized particles. We have studied lung retention and clearance kinetics in 12 healthy male adult WKY rats up to 6 mo after an inhalation of 192Ir-radiolabeled, insoluble, ultrafine 15- to 20-nm iridium particles. Whole-body retention was followed by external gamma counting, and particle clearance kinetics were determined by excretion radioanalysis. Four rats each were sacrificed after 3 wk and 2 and 6 mo; all organs as well as tissues and the carcass were radioanalyzed to balance the entire deposited radioactivity of the particles. The most prominant fraction was retained in the lungs at each time point of sacrifice (26%, 15%, 6%, respectively), and clearance out of the body was solely via excretion. Extrapulmonary particle uptake did not continue to increase but decreased with time in liver, spleen, heart, and brain when compared to previous data obtained during the first 7 days after inhalation (Kreyling et al., 2002). UFP long-term lung retention derived from whole-body measurements was comparable to previously reported data using insoluble micrometer-sized particles (Bellmann et al., 1994; Lehnert et al., 1989). In addition, differential analysis including daily excretion data revealed a pattern of fractional particle clearance rate of the ultrafine iridium particles similar to that of micrometer-sized particles reported by Snipes et al. (1983) and Bailey et al. (1985).

A new technique of 99mTc-ciprofloxacin kit preparation

Development of a simple and reproducible method for preparing a ciprofloxacin kit using a redox polymer, which would meet the requirements for an easy and reliable technique of labelling with 99mTc and diagnostic efficiency in scintigraphic imaging of infections. To prepare the kit, an insoluble redox polymer containing an end alpha(beta)-alanine-N,N'-diacetate group anchored to the dextran matrix was used. The redox polymer synthesised by the authors was incubated at room temperature (10 h) with a solution of ciprofloxacin (1%) in a suspension (5%). The mixture was then filtered and dispensed into sterile vials (0.2 ml each). The kit was labelled with 99mTc for 10 min at room temperature. The radiochemical purity of the ciprofloxacin-99mTc complex was determined by ITLC and paper chromatography in relation to the following factors: pH, total content of ciprofloxacin, volume of sodium 99mTc-pertechnetate. Ciprofloxacin biodistribution was evaluated in Wistar rats with Staphylococcus aureus infection in the left inguinal region 24 h after abscess induction. Accumulation of 99mTc activity was determined both using external gamma camera imaging and counting dissected tissues 1 h after administration. Radiochemical purity is > 95% for kit-labelling (pH 3.3-3.7). With pH 3.45, labelled ciprofloxacin shows the highest stability and radiochemical purity. The 99mTc-ciprofloxacin complex is stable for at least 8 h. In experimentally induced inflammation, the amount of accumulated 99mTc-ciprofloxacin activity is five times higher than in controls. The developed method of 99mTc-ciprofloxacin kit preparation employs a redox polymer in a new procedure, which enables the preparation of a stable kit with a high 99mTc-labelling efficiency. The labelled kit is suitable for scintigraphic imaging of infection.

Prevention of murine collagen-induced arthritis in the knee and ipsilateral paw by local expression of human interleukin-1 receptor antagonist protein in the knee.

To determine the efficacy of local human interleukin-1 receptor antagonist (HuIL-1Ra) gene therapy in murine collagen-induced arthritis (CIA). DBA/1 mice were immunized against bovine type II collagen. Before the onset of arthritis, NIH/3T3 fibroblasts transfected with pMFG-IRAP were transplanted into the knee cavity. Normal NIH/3T3 cells served as controls. Paws were evaluated macroscopically for redness, swelling, and deformities during the course of arthritis. Swelling of the knee joints was measured by external gamma counting of 99mtechnetium accumulation in the joint. Paws and knee joints were dissected and processed for histologic studies to evaluate inflammation and cartilage destruction. The NIH/3T3 fibroblasts survived in the joint cavity of DBA mice for at least 7 days. The transduced cells expressed immunoreactive and bioactive HuIL-1Ra in the knee joint, and produced sufficient amounts to block the effect of 1 ng of recombinant murine IL-1alpha on chondrocyte proteoglycan synthesis. The onset of CIA was almost completely prevented in knee joints containing HuIL-1Ra-producing cells, whereas joints containing normal cells showed severe inflammation and destruction of cartilage. Moreover, onset of CIA in the draining joints (ipsilateral paws) of the HuIL-1Ra gene-bearing knees was also prevented. Local production of HuIL-1Ra in the knee was able to ameliorate the effects of IL-1 on cartilage and could prevent the onset of CIA not only in that knee, but also in the "draining" paw. This indicates the feasibility of gene transfer as a therapeutic approach to modulating arthritis.

Hepatobiliary excretion of bacterial formyl-methionyl peptides in rat

The bacterial chemotactic peptide formyl-met-leu-phe and its radioiodinated analog formyl-met-leu-[125I]tyr are rapidly excreted by the liver into bile following portal or systemic venous infusions in rats or after absorption from the gut lumen. To determine the molecular structural requirements for hepatobiliary excretion of formyl-methionyl peptides, structure-activity studies using portal venous infusions of 24 structural analogs of formyl-met-leu-tyr were performed in rats with biliary cannulae. Hepatic extraction of peptides was studied in vivo using external gamma counting after portal infusion. Efficient hepatobiliary excretion was not restricted to bioactive formyl peptides, but showed a broad specificity for different amino-acylated (formyl, acetyl, propionyl, carbobenzoxy) di- and tripeptides and no requirement for methionine in position one or for a free carboxy terminus. However, nonacylated peptides and an acyl-amino acid showed little excretion. Hepatic extraction of peptide was also related to N-acylation. Hepatic extraction and excretion of N-acyl peptides were also related to hydrophobicity. Thus, the presence of an N-acyl group is the key determinant of biliary excretion of inflammatory bacterial f-met peptides in the rat.

Thrombolysis with bolus injections and infusions of tissue-type plasminogen activator in rabbits with experimental jugular vein thrombosis

The thrombolytic properties of 0.25, 1.0 and 2.0 mg/kg of recombinant tissue-type plasminogen activator (rt-PA) administered either as a bolus injection over 10 min or as a continuous intravenous infusion over 30 min or over 4 h were compared in rabbits with a 0.35 ml 125I-fibrin labelled autologous plasma clot in the jugular vein. The initial rate of clot lysis (expressed as percent per min) was determined by continuous external gamma counting during the initial 30 min after the start of the administration and the extent of clot lysis by radioisotope recovery at 4.5 h. The initial rate of clot lysis was independent of the dose when given as a 10 min bolus (0.54±0.04−0.64±0.05% lysis/min) or as a 30 min infusion (0.44±0.02−0.59±0.03% lysis/min) but was dose-dependent when rt-PA was infused over 4h (0.13±0.01−0.67±0.03% lysis/min). The initial rate of lysis with 2.0 mg/kg rt-PA was independent of the administration scheme (0.59±0.03−0.67±0.03% lysis/min), whereas with 0.25 or 1.0 mg/kg, the initial rate of lysis was higher when rt-PA was given as a bolus than as a 4h infusion (respectively 0.54±0.04 and 0.13±0.01% lysis/min with 0.25 mg/kg and 0.52±0.04 and 0.38±0.02% lysis/min with 1.0 mg/kg). Thus, a maximal initial rate of clot lysis of about 0.6% per min is reached at an infusion rate of about 8 μg/kg/min. The extent of clot lysis within 4.5 h was dose-dependent for each administration scheme, and at the highest dose (2.0 mg/kg) it was proportial to the duration of the infusion (42±3, 54±4 and 78±9% for bolus injection, 30 min infusion and 4 h infusion respectively). These findings indicate that the initial rate of clot lysis in vivo is saturable and that the maximal extent of clot lysis is obtained with a continuous infusion at a rate which does not exceed that producing the maximal initial rate of clot lysis.

Effect of longstanding venous stasis and hypoproteinaemia on lymph flow in the rat tail

This study was performed to provide information on the determinants of lymph flow by comparing the effect of venous stasis and hypoproteinaemia in the rat tail. This low-compliant tissue was chosen in an attempt to induce preferential changes in interstitial pressure or volume. The removal rate (kAlb) of 125I-labelled human serum albumin (I-HSA) injected subcutaneously was monitored with external gamma-counting equipment and used as a measure of lymph flow. Interstitial fluid hydrostatic pressure (Pi) was measured with wick-in-needle technique, and interstitial fluid was collected post mortem by dry wicks. Colloid osmotic pressure of plasma (COPp) and wick fluid (COPi) was measured with a colloid osmometer. In a separate group of experiments, 51Cr-EDTA and [125I]HSA were used to measure the interstitial fluid volume. Venous stasis, induced by bilateral ligation of the external tail veins, increased interstitial fluid hydrostatic pressure from 1.7 to 16 mmHg and kAlb from 0.030 to 0.063 h-1, whereas tail circumference was nearly constant. Interstitial volume averaged 1.17 ml/g dry weight in control animals and 1.27 ml/g during increased venous pressure. Daily injections of aminonucleoside in salt-loaded rats (0.3% NaCl as drinking water) reduced colloid osmotic pressure of plasma from 19.1 to 8.5 mmHg and of wick fluid from 11.2 to 2.9 mmHg, while interstitial fluid hydrostatic pressure increased to 5.2 mmHg. The removal rate of 125I-labelled human serum albumin increased to 0.113 h-1, compared to 0.051 h-1 in salt-loaded controls. The interstitial volume showed a marked increase in salt-loaded hypoproteinaemic rats, 1.75 ml/g dry weight, compared to 1.30 ml/g in salt-loaded controls.(ABSTRACT TRUNCATED AT 250 WORDS)

α-Amylase (EC 3.2.1.1) susceptibility rather than viscosity or gastric emptying rate controls plasma responses to starch in healthy humans

The relationship between starch alpha-amylase (EC 3.2.1.1) susceptibility, plasma responses and gastric emptying rates has been investigated in humans. Nine randomly chosen healthy subjects were given three carbohydrate test meals (25 g starch or equivalent glucose units): two maize starch pastes with (a) 240 (S24) or (b) 500 (S50) g amylose/kg, and a glucose solution (GS). At 30 min, in vitro starch alpha-amylolysis was 48 (SD 4)% for S24 and 35 (SD 4)% for S50. Test meals differed in viscosity (mPa x s: S24, 54,000; S50, 190; GS, 4). Carbohydrates were labelled with 99mTechnetium and isotope gastric emptying was measured by external gamma counting. Carbohydrate isotopic gastric emptying patterns were exponential. Half gastric emptying time (min) was significantly (P less than 0.05) shorter for S50 (19(SD 2] than for GS (26(SD 2] or S24 (29(SD 2]. No correlation was found between half gastric emptying time and plasma response values. Values for peak insulin (pmol/l) above fasting were significantly (P less than 0.05) different: GS, 306 (SD 11); S24, 227 (SD 11); S50, 187 (SD 11). It is concluded that alpha-amylase susceptibility of the test carbohydrates is a determining factor in the insulin response of healthy subjects, while viscosity of the test meals and gastric emptying rate have no effect.

A hamster pulmonary embolism model for the evaluation of the thrombolytic and pharmacokinetic properties of thrombolytic agents

A pulmonary embolus model in adult hamsters (body weight less than 100 g) was developed for the quantitative evaluation of the thrombolytic and pharmacokinetic properties of plasminogen activators. A clot was made from a mixture of 125I-labeled fibrinogen, citrated human plasma, thrombin and CaCl 2, and was injected into the jugular vein of heparinized hamsters. The time course of in vivo clot lysis was continuously measured with an external gamma counter, placed over the thorax. The extent of thrombolysis within 90 min was determined both as the difference between the initial and final external gamma count and as the difference between the radioactivity injected in the jugular vein and that recovered in the heart and lungs. In control animals infused with solvent for 60 min, spontaneous progressive clot lysis occurred resulting in 25 ± 1 % lysis (mean ± SEM; n = 87) by ex vivo isotope recovery and in 15 ± 2% lysis (n = 31) by external gamma counting. Recombinant tissue-type plasminogen activator (Activase®), recombinant single chain urokinase-type plasminogen activator (rscu-PA) and urokinase (Winkinase®), infused intravenously over 60 min, caused dose-dependent progressive thrombolysis. With 1.0 mgAkg Activase®, lysis was 91 ± 3% (n = 4) by ex vivo isotope recovery and 61 ± 6% (n = 4) by external gamma counting. With streptokinase (Streptase®) infusion or with bolus injection of anisoylated plasminogen streptokinase activator complex (Eminase®), dose-response curves were not linear. Fibrinogen and α 2-antiplasmin levels at the end of the experiments were unchanged with Activase® and rscu-PA, and moderately decreased with Winkinase®, Streptase® and Eminase®. Linear regression analysis of all results of the percent lysis at 90 min, determined by ex vivo isotope recovery (IR) and by external gamma counting (EC) (n = 101) yielded the equation (IR) = 1.08 (EC) + 21 with r = 0.87. The failure rate of the thrombolysis experiments, due to technical reasons or to death of the animals, was less than 5 %. After i.v. bolus injection of plasminogen activators in hamsters, the pharmacokinetic properties were determined from the disappearance rate of antigen from plasma, which were for Activase®, i.e., an initial half-life of 1.5 min and a plasma clearance of 2.8 ml/min. The hamster pulmonary embolism model is simple, reproducible, quantitative, and allows for one investigator to perform up to 10 experiments per day. This model may be useful for the evaluation of the potency, fibrin-specificity and pharmacokinetics of thrombolytic agents.

Insulin‐induced Hypoglycaemia and Absorption of Injected Insulin in Diabetic Patients

The effect of insulin-induced hypoglycaemia (soluble insulin 1 mU kg-1 min-1 IV) on the absorption of 125I-labelled soluble insulin (10 U SC) from thigh was studied in 10 insulin-treated Type 1 diabetic patients on a test and a control day. Disappearance of 125I was followed by external gamma counting. Adipose tissue blood flow was measured concomitantly using the 133Xe-clearance technique. Arterial plasma levels of glucose, insulin, adrenaline and noradrenaline were determined intermittently. Hypoglycaemia occurred at a glucose level of 2.2 +/- 0.1 (+/- SE) mmol l-1 after 58 +/- 6 min. Peak levels of adrenaline (6.44 +/- 1.62 nmol l-1) and noradrenaline (2.29 +/- 0.39 nmol l-1) were found 10 min later. During the 30-min period after onset of hypoglycaemia, adipose tissue blood flow increased 132 +/- 45% (p less than 0.05) but the disappearance rate of 125I-insulin was unchanged. Thus, insulin absorption was unaltered in connection with hypoglycaemia in Type 1 diabetic patients, in contrast to the depression previously reported in healthy subjects, despite similar increases in adipose tissue blood flow.

Toffee clearance and lingual sensory and motor activities in normal children and in children with articulation problems of speech

The rate at which a standardized mouthful of toffee containing technetium (99 mTc) tin colloid was cleared from the mouth during and after chewing was measured by counting the residual radioactivity in the mouth at short time intervals by external gamma counting. The clearance curve was resolved into three phases for each subject—chewing time (1), which coincided with the time to reach 10% of the initial counting rate, scavenging time (2), and a final slow diffusion phase (3). Although the mean chewing time was only 1.9 min, the technique allowed the pattern of clearance during this phase to be assessed for each of 10 normal children (mean age 11.1 yr) and 7 children (mean age 11.0 yr) diagnosed as having delayed articulation. Two measurements of sensory and motor functions of the tongue were made on the same subjects. These measurements were of oral stereognosis and tongue-tip manipulation. Within the control group, only the correlation between stereognosis error scores and the duration of phase 1 or phases 1 and 2 combined was statistically significant. The mean stereognosis and tongue manipulation scores were significantly lower in the poor articulation group than in normal children but, with one notable exception, the clearance curves were similar.

Insulin absorption and subcutaneous blood flow in normal subjects during insulin-induced hypoglycemia.

We studied the effects of insulin-induced hypoglycemia on the absorption of 10 U 125I-labeled soluble human insulin injected sc in the thigh in 10 normal subjects. The disappearance of 125I from the injection site was followed by external gamma-counting. Subcutaneous blood flow (ATBF) was measured concomitantly with the 133Xe washout technique. The plasma glucose nadir [mean, 2.0 +/- 0.1 (+/- SE) mmol/L] occurred at 33 +/- 3 min and resulted in maximal arterial plasma epinephrine concentrations of approximately 6 nmol/L. From 30 min before to 60 min after the glucose nadir the [125I]insulin absorption rate was depressed compared to that during normoglycemia. The first order disappearance rate constants were reduced by approximately 50% (P less than 0.01) during the first 30-min interval after the glucose nadir. During the same period ATBF increased by 100% (P less than 0.05). The results suggest that in normal subjects the absorption of soluble insulin from a sc depot is depressed in connection with hypoglycemia, despite considerably elevated ATBF.

Potent mental stress and insulin absorption in normal subjects.

Effects of mental stress (a 20-min modified Stroop's color-word conflict test; CWT) on the absorption of 125I-labeled soluble human insulin (10 U s.c. in the thigh 60 min before CWT) and on subcutaneous adipose tissue blood flow (ATBF; 133Xe clearance); heart rate (HR); arterial blood pressure (BP); and arterial levels of epinephrine (Epi), norepinephrine (NE), and glycerol were studied in 11 healthy subjects. Insulin absorption was measured as elimination of radioactivity (external gamma-counting) and as appearance of plasma immunoreactive insulin (IRI). The glucose-clamp technique was used to maintain normoglycemia. Identical measurements were performed during a control day without CWT. HR and mean BP increased markedly (35 +/- 5 beats/min and 30 +/- 3 mmHg) during CWT despite only minor elevations in plasma catecholamines. Thus, arterial plasma Epi rose from 0.18 +/- 0.03 to 0.82 +/- 0.17 nM (P less than .01) and NE from 0.94 +/- 0.09 to 1.69 +/- 0.18 nM (P less than .001). ATBF showed a biphasic response, with a 100% elevation during CWT followed by a decrease and a second peak of similar magnitude approximately 0.5 to 1 h after CWT. Blood glycerol was approximately doubled during CWT and remained elevated during recovery. Despite these changes, insulin absorption was unaltered during and after stress. Thus, elimination rates of 125I, plasma IRI levels, and amounts of glucose needed to maintain normoglycemia were all similar during the stress and control days. These results suggest that absorption of soluble insulin from subcutaneous injection sites in the thigh is unaltered during potent mental stress in healthy subjects despite a considerable and prolonged increase in ATBF.

A modified method for the simultaneous determination of regional single-transit brain extraction of diffusion-limited compounds and cerebral blood flow: Utilization of non-invasive measurement of transit time

A dual-label radioisotope method to measure regional cerebral blood flow (CBF) with [ 14C]butanol and the single-transit brain extraction of [ 3H]water (E w) was modified to permit concomittant measurement of the exit time through the cerebrovasculature of a bolus (BET) of 51chromium ( 51Cr)-labeled ethylenediaminetetraacetic acid (EDTA) in rodents. First, [ 51Cr]EDTA was injected intravenously via the femoral vein and its transit through cerebrovasculature determined by external gamma counting. The BET measurement was then used to determine the optimum time for animal sacrifice for subsequent measurement of CBF and E w to minimize both intravascular contamination and washout of butanol and water. This procedure resulted in higher CBF at moderate hypercapnia and slightly lower E w as a function of arterial CO 2 content than previously found using a fixed interval for sacrifice.

Orthostatic hypertension. Pathogenetic studies.

Among 1800 referred hypertensive patients, 181 had recumbent diastolic blood pressures (DBP) below 90 mm Hg and standing DBP above 90 mm Hg. Orthostatic increments in DBP were greater in these orthostatic hypertensive patients than in 181 persistently hypertensive patients and 134 normotensive subjects. In 12 patients with orthostatic hypertension, the orthostatic fall in cardiac output (27.3 +/- 2.9%, measured by a respiratory method) was double that in 8 normotensive subjects (13.3 +/- 3.7%, p less than 0.01). An inflated pressure suit over the pelvis and lower limbs prevented the excessive fall in cardiac output and significantly reduced (p less than 0.02) the excessive rise in standing DBP in orthostatic hypertensive patients. Gravitational pooling of blood in the legs and reduction of blood in the head was measured by external gamma counting of autologous erythrocytes labeled with sodium pertechnetate Tc 99m through ports in fixed positions over the leg and the temple. Orthostatic intravascular pooling was significantly greater (p less than 0.01) in orthostatic hypertensive subjects than in normotensive subjects, and the magnitudes of orthostatic pooling and orthostatic increases in DBP were closely correlated (r = +0.85). Plasma norepinephrine concentrations were similar in recumbency and after sustained handgrip exercise, but significantly greater (p less than 0.01) after 5 to 60 mins of standing in orthostatic hypertensive subjects than in normotensive subjects. Our results indicate that orthostatic hypertension is common and that its mechanism in representative patients involves excessive orthostatic blood pooling, which results in decreased venous return, decreased cardiac output, increased sympathetic stimulation (presumably through low-pressure cardiopulmonary receptors), and excessive arteriolar, but not venular, constriction.

Quantitation of arthritis by 99mTc-uptake measurements in the mouse knee-joint: correlation with histological joint inflammation scores.

A method is described to detect and to quantitate inflammation in knee-joints of mice. Approximately 10 muCi 99mTechnetium pertechnetate (99mTc) is injected subcutaneously in the neck region and the accumulation of the short-lived isotope in the knee-joint is detected by external gamma counting. 99mTc-uptake values correlate well with histological grading of joint inflammation at various intervals after induction of the inflammation. The method can be used to detect changes in activity of unilateral as well as bilateral joint inflammation using either the ratio of 99mTc uptake in the right knee versus that in the left knee or absolute 99mTc-uptake values.

Deposition and clearance of inhaled diesel exhaust particles in the respiratory tract of Fischer rats.

The fate of inhaled diesel particles was determined in male Fischer 344 rats using radioactive tracers of 131Ba and 14C. Test animals were exposed in a 'nose-only' inhalation chamber for 40-45 min to diluted diesel exhaust generated from diesel engines burning type 2D diesel fuel containing either 131Ba labelled barium dodecylbenzene sulfonate or 14C labelled n-hexadecane. Immediately after exposure, the deposition efficiency of inhaled diesel particles in the respiratory tract was determined to be 15 +/- 6% by external gamma counting of 131Ba and 17 +/- 2% by liquid scintillation counting of 14C in the lung tissue samples. Elimination of the particles was observed by measuring the 131Ba activity in which 40% of the initial deposition was excreted in the feces via the GI tract in 4 days. The long-term retention was determined with the 14C tag in the insoluble 'core' of the diesel particles. Two distinct phases of clearance were evident in the experimental data collected up to 105 days. Clearance half-times of 1 day and 62 days were found for mucociliary and alveolar clearance, respectively. A small fraction of the particles, about 6% of the initial deposition, was found in the mediastinal lymph nodes after 28 days. This demonstrated that the lymphatic system was also involved in the removal of diesel particles from the pulmonary airways.

Inhibition of hepatic binding of thyroxine by cholecystographic agents.

Subsequent to studies indicating that cholecystographic agents and sulfobromophthalein (BSP) inhibit uptake of thyroxine (T(4)) by rat liver slices, the effect of such compounds on hepatic storage of T(4) in man has been examined. After intravenous administration of [(125)I]T(4) to five normal subjects, hepatic radioactivity, estimated by external gamma counting, rose to a peak in approximately 4 h and then declined in parallel with serum radioactivity. When a 6-g dose of the cholecystographic agent, tyropanoate (Bilopaque), was administered orally 3 d later, estimated hepatic extravascular radioactivity fell 50-60% within 4 h and then rose toward the pretyropanoate value. Concomitant with the fall in hepatic radioactivity, serum radioactivity rose 57-70%, as did stable T(4) levels in serum, suggesting that hormone discharged from the liver entered the serum. Both uptake of T(4) and discharge by tyropanoate were much less in two patients with liver disease. Ipodate (Oragrafin), 12 g orally in two subjects, caused much smaller changes in hepatic and serum radioactivity. However, ipodate also caused a doubling of the percent free T(4) in the serum as judged by equilibrium dialysis, and the ratio of hepatic radioactivity to free [(125)I]T(4) in serum declined markedly after ipodate, similar to the fall in hepatic:serum (125)I ratios after tyropanoate. BSP, 20 mg/kg i.v. in three subjects, caused a smaller change; the decline in hepatic T4 content averaged 19%. We conclude that these organic anions, tyropanoate, ipodate, and BSP, all can displace T(4) from the liver. The results imply a link between T(4) transport and organic anion transport, and indicate a mechanism for altering hepatic T(4) content in man that could be the site of physiologic regulation or of disease. A method is described whereby analysis of the change in hepatic and plasma radioactivity after tyropanoate could be employed to estimate hepatic T(4) content in diverse clinical circumstances.

Prolongation of gastric emptying by oral propantheline

The present study shows that a single oral recommended dose of propantheline bromide normally doubles the mean gastric half-emptying time in man. In a prospective, double-blind, randomized crossover design 13 normal subjects were given 30 mg propantheline or placebo 90 min before taking a 113m-indium-labeled liquid test meal, the volume of which was adjusted to body weight. The disappearance of radioisotope from the area of the stomach was determined by external gamma counting. After placebo the mean half-emptying time was 68 min and after propantheline it was 135 min (p less than 0.005). Although salivary flow decreased and pulse rate increased there were no visual disturbances. In studies already reported maximally tolerated oral doses of quaternary ammonium anticholinergic drugs have not consistently retarded gastric emptying in man.

Effect of adrenergic agents and their mode of action on mucociliary clearance in man.

The aerosolized adrenergic (ADR) agent, isoproterenol (ISO), was found markedly to accelerate mucus clearance within the human tracheobronchial tree. Mucus transport was measured by external gamma counting of aerosolized Fe2O3 particles deposited on the mucous membrane during inhalation. Aerosolized epinephrine (EPI), despite its alpha-ADR bronchial vasoconstrictor activity, increased mucus clearance to the same degree as did aerosolized ISO, with its beta-ADR bronchial vasodilator activity. The vehicle used for delivery of the ADR agents, i.e., a H2O aerosol by intermittent positive-pressure breathing (IPPB), itself increased mucus clearance slightly, but did not elicit the enormous increases produced by the ADR agents. Parenteral ISO caused increases in clearances similar to aerosolized ISO and EPI (consistent with different tissue drug levels achieved). Oral atropine delayed clearance, but atropine prior to an ADR aerosol did not alter the mucus transport effect of the ADR agent. ISO and atropine, despite opposite effects on mucus clearance, caused equal bronchodilation. Thus, increased clearance following aerosolized ISO was not dependent on bronchial vasodilation, aqueous aerosol droplets, reflex parasympathetic activation, or bronchodilation, and seems best attributable to increased ciliary beat rate.