Michel De Roo

Comparison of total and compartmental gastric emptying and antral motility between healthy men and women

Abstract. There is increasing evidence of gender-related differences in gastric emptying. The purpose of this study was first, to confirm the difference in gastric emptying for both solid and liquid test meals between healthy men and women, and secondly, to investigate the origin of this difference by studying regional gastric emptying and antral motility. A standard gastric emptying test with additional compartmental (proximal and distal) evaluation and dynamic imaging of the antrum was performed in 20 healthy women studied during the first 10 days of the menstrual cycle, and in 31 healthy age-matched men. In concordance with previous reports, women had a longer half-emptying time for solids as compared to men (86.2±5.1 vs 52.2±2.9 min, P<0.05). In our observations this seemed to be related to a significantly prolonged lag phase and a significant decrease in terminal slope. Dynamical antral scintigraphy did not show a significant difference. The distribution of the test meal within the stomach (proximal vs distal) showed more early proximal retention in women as compared to men. The terminal slope of the distal somach was significantly lower in women. We did not observe a significant difference in gastric emptying of the liquid test meal between men and women. Gastric emptying of solids is significantly slower in healthy women as compared to men. These findings emphasise the importance of using different normal values for clinical and research purposes in gastric emptying scintigraphy in men and women. The difference could not be explained by antral motility alone. Increased proximal retention and a lower terminal emptying rate in women are observations to be further investigated.

First experience in healthy volunteers with technetium-99m l,l-ethylenedicysteine, a new renal imaging agent

Animal studies have indicated that technetium-99m l,l-ethylenedicysteine (99mTc-l,l-EC) may be a promising tracer agent for renal function studies. We have performed a paired study with 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) and 99mTc-l,l-EC in six male volunteers. In both cases, iodine-131-labelled o-iodohippurate was co-injected as an internal biological standard. The analog images between 0 and 30 min p.i. were of identical diagnostic value for both tracer agents. The two renograms were similar in all volunteers. The mean 1-h plasma clearance for 99mTc-MAG3 and 99 mTc-l,l-EC was significantly different, respectively 382.9 ± 17.1 ml/min per 1.73 m2 versus 460.2 ± 47.7 ml/min per 1.73 m2 (P<0.003). The urinary excretion after 30 min p.i. was 69.4% ± 5.6% of the injected dose for 99mTc-MAG3 versus 66.5% ± 2.5% for 99mTc-l,l-EC (P>0.05) and after 60 min p.i. respectively 83.1% ± 3.9% versus 79.8 % ± 4.3 % (P > 0.05). 99mTc-l,l-EC has a very low plasma protein binding (31% ± 6.8%) as compared to 99mTc-MAG3 (88% ± 5.2%) and a larger volume of distribution. Although the exact mechanism responsible for the high plasma clearance of 99mTc-l,l-EC is not yet fully known, we conclude that this new agent merits further clinical evaluation in patients to establish its value as a renal radiopharmaceutical.

Effect of motilin on gastric emptying in patients with diabetic gastroparesis

Erythromycin markedly accelerates gastric emptying, possibly because it acts as a motilin agonist. In the present study, the effect of an equipotent dose of motilin was tested. In six patients with severe diabetic gastroparesis, gastric emptying of liquids and solids was examined scintigraphically after motilin or placebo in a double-blind crossover study. Motilin (10 pmol.kg-1.min-1) or saline was infused over a 90-minute period starting 5 minutes before breakfast. Motilin markedly accelerated emptying. For liquids, the half-emptying time was reduced from 51 +/- 6 to 22 +/- 11 minutes (P less than 0.01) and for solids from 111 +/- 4 to 51 +/- 12 minutes (P less than 0.01). The mean increase in plasma motilin levels was 1315 +/- 342 pg/mL, corresponding to an effective infusion rate of about 4 pmol.kg-1.min-1. In the control experiments, basal motilin levels (173 +/- 17 pg/mL) were within the normal range but increased steadily postprandially, reaching 321 +/- 25 pg/mL at the end of the study period, probably reflecting gastric distension. The postprandial increase in pancreatic polypeptide level was blunted compared with accepted normal values but was more pronounced during motilin infusion, i.e., 650 +/- 217 vs. 279 +/- 66 pg/mL (P less than 0.01), probably because of the improved emptying. Our data show that motilin accelerates gastric emptying in diabetic gastroparesis and support the hypothesis that erythromycins effect is mediated through motilin receptors.

Evaluation of small bowel transit for solid and liquid test meal in healthy men and women

Abstract. Evaluation of severe functional gastrointestinal motility disorders requires an investigation of the entire gastrointestinal tract. This should be possible with a single radionuclide imaging study. The purpose of this study was (1) to define normal values of small-bowel transit in men and women and (2) to assess a possible difference between gender or test meal, since it has been shown that women have slower gastric emptying than men, and gastric emptying of solids is slower than liquids. A standard gastric-emptying test for a solid (technetium-99m sulphur colloid, 230 Kcal) and liquid (indium-111 DTPA water) test meal was performed in 12 healthy male and 12 healthy female volunteers. After 135 min, the volunteer was placed in the supine position for static imaging of the abdomen every 15 min for 6 h. Decay and crossover-corrected geometric mean gastric-emptying data were fit to a modified power exponential function to determine the 10% stomach emptying time for solids and liquids separately. An ROI was drawn around the caecum and ascending colon to determine the arrival time of at least 10% of the solid and liquid test meal. Ten percent small-bowel transit time (10%SBTT) and orocaecal transit time (OCTT) were calculated.The OCTT for males and females, respectively for solids and liquids, are 294.6±18.8; 301.3±24.5; 294.6±18.8 and 301.3±24.5 min. The 10%SBTT for males and females, respectively for solids and liquids, are 280.3±18.4; 280.6±24.0; 288.2±18.9 and 297.4±24.4 (mean±SEM) min. We observed a simultaneous transfer of solids and liquids from the terminal ileum to caecum (correlation coefficient 0.90). There is no statistically significant difference in SBTT between gender or solids and liquids. In contrast to the gastric-emptying time, the SBTT of solids and liquids were not significantly different nor was a gender difference found. Determination of the OCTT seems to be the simplest and most accurate approach to measure SBTT. Since ileocaecal transfer occurs as a bolus phenomenon, a 111In-labelled test meal can also be used for the determination of colon transit in a single imaging study protocol.

Seasonal variation in bone metabolism in young healthy subjects

SummarySerum vitamin D metabolites and urinary calcium excretion; parameters of bone formation (serum alkaline phosphatase, serum osteocalcin); parameters of bone resorption (24 hour hydroxyprolinuria, 2 hour fasting urinary hydroxyproline/creatinine ratio); and parameters of cortical and trabecular bone density, parathyroid hormone (iPTH, COOH terminal assay), and serum minerals (calcium, phosphorus) were followed serially in 55 young adults (21 women and 34 men) from December 1985 until January 1987 at four different times during the year. The effect of a low-dose cyclooxygenase inhibitor (piroxicam 5 mg daily) on the same parameters of bone density and bone turnover when given from December until May, was also evaluated in this study. At the end of the treatment period parameters of bone turnover and bone density were comparable between placebo and piroxicam-treated groups. Therefore, the results of all subjects were pooled in order to investigate seasonal variation. In both sexes, seasonal variation was found not only for 250HD3 but also for 1,25(OH)2D3, serum calcium and phosphorus, urinary calcium excretion, and for bone density at the lumbar spine. Parameters of bone formation (serum osteocalcin and alkaline phosphatase), bone resorption (24 hour urinary hydroxyprolinuria and fasting urinary hydroxyproline/creatinine ratio) and PTH were influenced by this seasonal variation. We conclude that in young adults, a significant seasonal variation occurs, with low winter and high summer values, for serum 25 and 1,25(OH)2D3 for urinary calcium apparently without important influence on parameters of bone turnover or parathyroid activity and for lumbar spine density. Treatment with a low-dose cyclooxygenase inhibitor was without influence on the observed changes.

Complexes of technetium-99m with tetrapeptides, a new class of 99mTc-labelled agents

Tetrapeptides are a class of N4-tetraligands that can efficiently bind 99mTc. In fact, tetrapeptides can be considered as derivatives of mercaptoacetyltriglycine (MAG3) in which the mercaptoacetyl moiety is replaced by a more stable and easier to handle aminoacyl group. Direct labelling of tetrapeptides with 99mTc in alkaline medium (pH > or = 11) in the presence of stannous ions gave a high yield (> 95%) of one or two (probably isomeric) radiochemical species. Exchange labelling at different pH values in the presence of stannous tartrate resulted in lower yields of the same 99mTc-labelled products as those formed during direct labelling. In addition, other radiochemical species were formed of which one was characterized as an oxotechnetium-complex with the cyclisized tetrapeptide. Tetrapeptides with a chiral centre in the first amino acid yield upon labelling with 99mTc two radiochemical species, probably the two diastereomers with an oxotechnetium core respectively syn and anti with respect to the substituent on the amino acid. Only one diastereomer was observed when the chiral carbon atom is located in the second or third amino acid. Electrophoresis indicated that these new 99mTc-labelled complexes are neutral in acidic medium and negatively charged in neutral and alkaline conditions. This correlates with a complex in which an oxotechnetium(V) group is bound to the ligand through three deprotonated nitrogen atoms of the amide functions and the free electron pair of the amine nitrogen atom. Biodistribution in mice showed for all studied 99mTc-labelled tetrapeptides a rapid clearance from the blood mainly by the renal system. The presence of a methyl substituent in the tetrapeptide increased the urinary excretion. 99mTc-labelled L-glycylalanylglycylglycine showed in mice a urinary excretion comparable to that of 99mTc-MAG3. Further rise of lipophilicity by introduction of a dimethyl, isopropyl or isobutyryl group leads to increased hepatobiliary handling. It is concluded that tetrapeptides are an interesting group of technetium complexing agents which can easily be labelled with 99mTc at room temperature in alkaline medium. This class offers the possibility of a wide variety of derivatives, just by substituting one or more amino acids. This group of ligands thus opens a new research field of 99mTc-complexes with potential usefulness in several areas.

Diffuse pulmonary uptake of 99mTc bone-imaging agents: Case report and survey

Over the past 5 years, we have encountered 6 cases of diffuse pulmonary uptake of 99m-Tc bone-scanning agents (incidence, 0.04%). To assess the significance of this phenomenon, we reviewed all of the cases reported since 1974 (Including our series, a total of 32 cases). Three groups can be discerned, the first consisting of 24 patients without radiological calcifications in the lungs and with hypercalcemia of different origins (mostly hyperparathyroidism). Of the eight autopsies performed in this group, seven revealed extensive calcifications in alveolar walls and lung vessels; the other autopsy showed no calcification at all and only bronchopneumonic lesions. The second group consists of 6 patients in chronic dialysis. The last group consists of 2 patients having diffuse pulmonary alveolar microlithiasis with extensive radiologic calcifications.The mechanism of lung uptake of 99m-Tc bone-imaging agents is probably the same as that of bone uptake (chemisorption on hydroxyapatite crystals), although other uptake mechanisms have also been discussed.Bone scintigraphy can be useful in the detection of early pulmonary calcifications, which have been associated with impaired pulmonary function and, due to their size, are generally not detected by X-ray.

Regional myocardial blood flow, glucose utilization and contractile function before and after revascularization and ultrastructural findings in patients with chronic coronary artery disease

In patients with chronic coronary artery disease, follow-up measurements of myocardial blood flow, metabolism and function were correlated with histology. In 41 patients with chronic coronary artery disease and a severely stenosed left anterior descending coronary artery, a positron emission tomographic (PET) flow/metabolism study and nuclear angiography were performed immediately before and 3 months after bypass surgery. Biopsies were taken from the left ventricular anterior wall at the time of surgery. Control biopsies were taken from donor hearts for cardiac transplantation and from hearts of patients with a defect of the atrial septum. A significant improvement of flow (P<0.01) and regional contractile function (P<0.01) was observed in the mismatch group. Glucose utilization was significantly lower (P<0.001) as compared to preoperative values. The group with preserved flow and the PET match group revealed no significant changes in flow, metabolism or function. Control biopsies revealed significantly less myolytic cells as compared to biopsies taken from both match and mismatch groups (P<0.01) and less fibrosis as compared to biopsies taken from the match group (P<0.01). Postoperatively, linear relationships were found between flow and both % fibrosis (r = 0.71,P<0.001) and regional anterior ejection fraction (r = 0.7,P<0.001). Only mismatch areas revealed significant recovery of both flow and function after revascularization with a disappearance of enhanced glucose uptake. The better linear correlation between flow and % fibrosis after surgery as compared to preoperatively was probably due to improvement of flow values in the mismatch group.

Technetium-99m mercaptoalbumin as a potential substitute for technetium-99m labelled red blood cells

Technetium-99m labelled red blood cells (99mTc-RBCs) are far superior to 99mTc-labelled human serum albumin (99mTc-HSA) for radionuclide ventriculography, but their labelling is more complex, time consuming and risk bearing (in vitro labelling) or suffers from interference by some medications (in vivo labelling). We have now modified HSA by the introduction of mercapto groups with the purpose of preparing stable and practical 99mTc-mercaptoalbumin with long retention in the vascular system, that could replace 99mTc-RBCs. HSA was incubated with N-succinimidyl S-acetylthioacetate (SATA) or N-succinimidyl 2,3-di(S-acetylthio) propionate (SATP) to introduce a chain containing one or two protected sulfhydryl groups on some of the lysine amino groups. After purification by size-exclusion chromatography (SEC), the mercapto groups were deprotected by incubation at alkaline pH or by treatment with hydroxylamine. The reaction products were used with or without SEC purification for direct or exchange labelling experiments with 99mTc at neutral pH. SEC-HPLC was used to determine labelling yields and to isolate pure 99mTc-mercaptoalbumin. Stable 99mTc-mercaptoalbumin complexes could be formed in 90%–95% yield after coupling albumin with SATA or SATP in all molar ratios used followed by deacetylation in one of the mentioned conditions. The most favourable results were obtained after reaction of SATA or SATP with HSA in a 25: 1 ratio and deprotection with NH2OH. The stability of the resulting 99mTc-mercaptoacetyl-albumin (99mTc-MAHSA) and 99mTc-dimercaptopropionyl-albumin (99mTcDMP-HSA) and their retention in vivo in plasma of mice and rabbits are clearly higher than that of conventional 99mTc-HSA preparations. 99mTc-DMP-HSA approaches the behaviour of 125I-HSA quite well in both animal species. A preliminary study with 99mTc-DMP-HSA in a volunteer showed a retention in the vascular compartment almost identical to that of 99mTc-RBCs and clearly higher than that of a common 99mTc-HSA preparation. The results indicate that these 99mTc-mercaptoalbumins and especially 99mTc-DMP-HSA are very promising as a practical alternative to 99mTc-RBCs.

Complexes of technetium-99m with tetrapeptides containing one alanyl and three glycyl moieties.

Recently, we have shown that tetrapeptides can be efficiently labelled with technetium-99m by direct labelling at alkaline pH. Tetrapeptides can be considered derivatives of mercaptoacetyltriglycine (MAG3) in which the mercaptoacetyl moiety is replaced by an amino acid residue. In view of the interesting biological properties of some C-methyl substituted derivatives of99mTc-MAG3, we have now synthesised and evaluated the complexes of99mTc with tetrapeptides containing three glycyl (G) moieties and oned- orl-alanyl (A) moiety. In mice,99mTc-l-GAGG,99mTc-d-GGAG and99mTc-l-GGAG showed a rapid and high renal excretion, comparable to that of99mTc-MAG3. Renal handling was somewhat reduced for isomersd andl of99mTc-AGGG and99mTc-d-GAGG and markedly inferior for99mTc-l-GGGA and99mTc-d-GGGA. In the baboon,99mTc-l-AGGG,99mTc-d-AGGG and99mTc-l-GAGG showed a comparable or even higher 1-h plasma clearance than99mTc-MAG3.99mTc-d-GAGG,99mTc-l-GGAG and99mTc-d-GGAG were characterised by a lower plasma clearance and the clearance of99mTc-l-GGGA and99mTc-d-GGGA was remarkably low. The three99mTc-labelled tetrapeptides with the highest plasma clearance in a baboon were compared with99mTc-MAG3 in a human volunteer.99mTc-l-AGGG and99mTc-l-GAGG had a roughly similar plasma clearance as99mTc-MAG3. The clearance of99mTc-d-AGGG was significantly lower and liver uptake was clearly visible with this compound. Left kidney renograms of99mTc-l-AGGG and99mTc-d-AGGG indicated moderate kidney accumulation. On the other hand, the renogram obtained after injection of99mTc-l-GAGG had an excellent shape and the maximum kidney concentration was slightly higher than for99mTc-MAG3. These results show the importance of the position of the methyl substituent on the99mTc-tetrapeptide with respect to its biological behaviour.