Colonic transit studies with 99mTc-rhenium sulfide colloid in live rats. A preliminary study.

Abnormal colonic motility is associated with clinical relevant conditions such as irritable bowel syndrome or constipation. Accurate assessment of colonic transit in an animal model would be useful in studying these conditions and screen potential drug candidates. The aim of this study was to assess if scintigraphic analyses could reliably evaluate total and segmental colonic transit as a measure of colonic motility of a non-absorbable radiotracer in rats. Normal Lewis rats (250-300 g) were given oral technetium-99m-rhenium sulfide colloid (15-20 MBq; 0.5 mL; n=4) followed by a rinse with water for injection (1.0 mL). Rats were fed and hydrated ad libitum. After 30 min, each rat was contained inside an 'imaging' tube then placed on a g-camera collimator. Whole body 5 min static images were acquired every 30 min up to 9 h, and then finally at 25 hours. Region of interest analyses were applied to the caecum/proximal colon, sigmoidal loop and distal colon/rectum. The tracer entered into the colon at approximately 4 hours, and the rats remained static to permit 'live' imaging. At 4 hours the % whole body activity was: 51% caecum/proximal colon, 39% sigmoidal loop, 6% distal colon/rectum; at 8 hours, 30% caecum/proximal colon, 13% sigmoidal loop, 7% distal colon/rectum. In the whole colon there was < or =1% of total activity present at 25 hours, and the half clearance time was determined as 4.0 hours. These results suggest this is a reliable technique of measuring regional colonic transit as a measure of colonic motility in normal rats. This methodology might be well suited to screen potential motility effects of drug candidates.

Effects of protein on glycemic and incretin responses and gastric emptying after oral glucose in healthy subjects.

BACKGROUND: Dietary interventions represent a promising therapeutic strategy to optimize postprandial glycemia. The addition of protein to oral glucose has been reported to improve the glycemic profile. OBJECTIVE: The aim of the current study was to evaluate the mechanisms by which protein supplementation lowers the blood glucose response to oral glucose. DESIGN: Nine healthy men were studied on 3 d each in a random order. Subjects consumed 300-mL drinks containing either 50 g glucose (Glucose), 30 g gelatin (Protein), or 50 g glucose with 30 g gelatin (Glucose + Protein) in water labeled with 150 mg [(13)C]acetate. Blood and breath samples were subsequently collected for 3 h to measure blood glucose and plasma insulin, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) concentrations and gastric half-emptying time, which was calculated from (13)CO(2) excretion. RESULTS: The blood glucose response was less after Glucose + Protein than after Glucose (P < 0.005); GIP was lower (P < 0.005), and there were no significant differences in plasma insulin or GLP-1. Protein alone stimulated insulin, GLP-1, and GIP (P < 0.05 for each) without elevating blood glucose. The gastric half-emptying time was greater after Glucose + Protein than after Glucose (P < 0.05) and tended to be greater for Glucose than for Protein (P = 0.06). CONCLUSIONS: In healthy humans, the addition of protein to oral glucose lowers postprandial blood glucose concentrations acutely, predominantly by slowing gastric emptying, although protein also stimulates incretin hormones and non-glucose-dependent insulin release.

Liquid gastric emptying in the pig: effect of concentration of inhaled isoflurane.

UNLABELLED: An animal model of gastric emptying may have use in the study of gastric physiology and pharmacoscintigraphy. The pig has anatomy and physiology similar to that of humans. Our aim was to develop a model of gastric emptying in the pig. It was not possible to perform this study in conscious pigs; therefore, an anesthetic model was developed. METHODS: Fifteen studies were performed on 4 pigs (age, 2-6 mo; weight, 20-100 kg). After acclimatization and training, pigs were fasted overnight before the study. Pigs were anesthetized using inhaled isoflurane without the use of injected premedication agents. An orogastric tube was inserted for the administration of a liquid meal, which consisted of (99m)Tc-diethylenetriaminepentaacetic acid either in water (nonnutrient) or with dextrose (nutrient meal). The pig was laterally positioned to enable right lateral dynamic acquisition to be performed. Anesthesia was maintained at 2% +/- 0.5% isoflurane in 4 studies and 0.8% +/- 0.5% in 11 studies (4 nutrient, 7 nonnutrient). RESULTS: With 2% +/- 0.5% isoflurane, there was delayed gastric emptying with a mean 50% emptying time (+/-SEM) of 141 +/- 14 min. With 0.8% +/- 0.5% isoflurane, the liquid meal emptied in an exponential manner similar to that of humans, with mean 50% emptying times (+/-SEM) of 30 +/- 7 min (nutrient) and 31 +/- 4 min (nonnutrient). CONCLUSION: The results indicate that high-dose anesthesia inhibits gastric emptying, but with low-dose anesthesia a useful pig model of liquid gastric emptying can be developed.

Comparison of 99mTc-alafosfalin and 67Ga-citrate in a mouse model of bacterial infection.

BACKGROUND: The antibiotic-peptide (99m)Tc-alafosfalin was assessed as an infection imaging agent in Staphylococcus aureas infected mice by comparison with (99m)Ga-citrate, and also examined for influence of septic status on tracer biodistribution by comparison with normal mice. MATERIAL AND METHODS: Intramuscular doses of S. aureus were administered into the right thigh muscle of mice and the infection was allowed to develop for 20 hours. In separate experiments, (99m)Tc-alafosfalin and (67)Ga-citrate were subsequently administered and allowed to localise. Quantitative organ distribution studies were performed in conjunction with scintigraphic images at 1 and 4 hours post injection. An additional biodistribution with (99m)Tc-alafosfalin in normal mice was also performed. RESULTS: (99m)Tc-alafosfalin was predominantly renal excreted, with low liver, intestine and bone uptake. There was no difference in the uptake of these organs when infected mice were compared with normal mice. (99m)Tc-alafosfalin activity in the intestine at 1 and 4 hours was substantially less than (67)Ga-citrate. For (99m)Tc-alafosfalin, infected/non-infected thigh ratios of 2.8/1.0 and 3.6/1.0 were determined at 1 and 4 hours post injection respectively. (67)Ga-citrate gave ratios of 1.6/1.0 and 3.7/1.0 at the corresponding time points. CONCLUSIONS: (99m)Tc-alafosfalin uptake was more rapid than (67)Ga-citrate, yet diffuse at the infectious sites in mice. The small and juvenile mouse model resulted in uptake of the phosphonic acid tracer by active bone growth areas which may be a disadvantage. This (99m)Tc-antibiotic peptide has potential as an infection imaging agent, and will be investigated further in another rodent infection model in the future.

Host immune response determines visceral hyperalgesia in a rat model of post-inflammatory irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is associated with visceral hyperalgesia and frequently occurs after a transient gastrointestinal infection. Only a proportion of patients with acute gastroenteritis develop post-infectious IBS suggesting differences in host response to inflammatory stimuli. We aimed to investigate this concept by characterizing visceral sensitivity in two rat strains, following a chemically induced colitis. METHODS: Colorectal instillation of trinitrobenzenesulfonic acid (TNBS) in aqueous ethanol was used to induce a transient colitis in Lewis and F344 rats. The colitis was characterized semiquantitatively by histology, as well as by quantitative methods using (99m)Tc-leukocytes (radioactive organ assay) and plasma IL-2 and IL-6 levels. Visceromotor response to colorectal distensions was assessed after 2 h and, 5, 14, and 28 days. RESULTS: The colitis peaked on day 5 and dissipated to no visible mucosal damage on day 14. Cytokines were significantly increased in TNBS-treated rats at 2 h and on day 5. On day 14 cytokines were still significantly enhanced in Lewis but not Fisher rats. Both strains had a highly inflamed to non-inflamed tissue ratio at 3 h after TNBS instillation with increased uptake in Lewis compared to F344 rats. No (99m)Tc-tin-colloid-leukocytes were detected in colon samples on day 28. Visceromotor response was significantly elevated in both strains during the acute colitis (day 5), whereas only Lewis rats developed a post-inflammatory (day 28) visceral hyperalgesia. CONCLUSION: Genetically determined host factors account for prolonged immune activation in response to a standardized inflammatory stimulus and are linked to susceptibility for a post-inflammatory visceral hyperalgesia.

Anorectal dysfunction increases with time following radiation therapy for carcinoma of the prostate.

OBJECTIVES: To characterize the prevalence and pathophysiology of anorectal dysfunction up to 2 yr following radiation therapy (RT) for localized carcinoma of the prostate. METHODS: Thirty-eight patients, median age 68 (range 60-82) yr with localized prostate carcinoma randomly assigned to one of two radiation dose schedules, underwent evaluation of the following variables of anorectal function before RT, as well as 4-6 wk and 1 and 2 yr after its completion: (1) symptoms, (2) anorectal motility, (3) anorectal sensory function, and (4) anal sphincteric morphology. RESULTS: There was a persistent increase in anorectal symptoms after RT. At 2 yr, bowel frequency, urgency, and fecal incontinence were increased in 50%, 47%, and 26% of patients, respectively. After RT, there were progressive reductions of (1) basal anal pressures, (2) anal pressures in response to squeeze and increased intra-abdominal pressure, (3) rectal compliance, and (4) rectal volumes associated with sensory perception and the desire to defecate. The thickness of the external anal sphincter increased with time after RT. No difference was observed between the patients in the two radiation dose schedules. CONCLUSIONS: Anorectal dysfunction following RT for prostate carcinoma is an underestimated cause of morbidity, which progresses with time. The prevalence and pathophysiology of anorectal dysfunction is similar after treatment with two commonly used radiation dose schedules.