The adaptive response of the rat small intestine after resection and segmental transplantation during the early postoperative phase.

Organ harvesting from a living donor or spatial constraints in the recipient's abdominal cavity are the main factors to be considered in the segmental transplantation of the small intestine. It was the aim of the following study to gain insight into the functional characteristics of different portions of the small intestine either after partial resection or syngeneic and allogeneic transplantation during the early postoperative period. Nutritional parameters (serum albumin levels, serum triglyceride levels, maltose absorption, excretion of fecal fat) and fat-stimulated neurotensin release were determined in Lewis rats that underwent small bowel resection (n = 21), syngeneic (Lewis-->Lewis, n = 21), or allogeneic transplantation (Brown Norway-->Lewis, n = 24). The length of the remnant, isograft, or allograft was 27 cm (i.e. one third of the rat small intestine) and consisted of the proximal (n = 7), middle (n = 7), or distal (n = 7) portion. Three postoperative deaths were due to ileus or pneumonia. After allotransplantation, cyclosporine (15 mg/kg BW s.c.) was administered for graft acceptance. Controls were unoperated, weight- and age-matched Lewis rats (n = 7). We found that resection of two-thirds of the small intestine led to significantly lower levels of albumin and triglycerides in all the three portions investigated (P < 0.01) but did not affect maltose absorption. Excretion of fecal fat was elevated after distal resection (P < 0.05). When compared to resected animals, syngeneic transplantation did not affect the nutritional parameters, but caused a significantly higher hormone release (P < 0.05) in all three different intestinal grafts. Allogeneic transplantation was successful when the middle or distal portion was grafted. All recipients of proximal allografts showed a severe loss of body weight and died between day 8 and 10 after transplantation. Postmortem examination revealed no signs of acute rejection. When transplantation of short intestinal segments is considered, it is of vital importance to take into account the functional differences and the influence of immunosuppressive drug therapy in the regulatory bowel function.

[Metabolic parameters and neurotensin liberation after resection of the small intestine, syngeneic and allogeneic segment transplantation the rat]. / Stoffwechselparameter und Neurotensinfreisetzung nach Dünndarmresektion, syngener und allogener Segmenttransplantation an der Ratte.

The aim of the following study was to gain some insight into the functional characteristics of different portions of the small intestine after either partial resection or syngeneic and allogeneic transplantation 3 months postoperatively. Nutritional parameters (serum albumin levels, serum triglyceride levels, maltose absorption, excretion of fecal fat) and fat-stimulated neurotensin release were determined in Lewis rats that underwent small-bowel resection (n = 21), syngeneic (Lewis-->Lewis, n = 21), or allogeneic transplantation (Brown Norway-->Lewis, n = 24). The length of the remnant, isograft, or allograft was 27 cm (i.e., one-third of the rat small intestine) and consisted of the proximal (n = 7), middle (n = 7), or distal (n = 7) portion. Three postoperative deaths were due to ileus or pneumonia. After allotransplantation cyclosporine (15 mg/kg body wt. s.c.) was administered for graft acceptance. The control group was not operated upon, but was composed of weight- and age-matched Lewis rats (n = 7). We found that resection of two-thirds of the small intestine led to significantly lower levels of albumin and triglycerides in all three portions investigated (P < 0.01), but did not affect maltose absorption. Excretion of fecal fat was elevated significantly only after distal resection (P < 0.05). When compared to resected animals, syngeneic transplantation did not affect the nutritional parameters, but caused a significantly higher hormone release (P < 0.05) in all three different intestinal grafts. Allogeneic transplantation was successful when the middle or distal portion was grafted. All recipients of proximal allografts showed a severe loss of body weight and died between day 8 and 10 after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of CCK in regulation of pancreaticobiliary functions and GI motility in humans: effects of loxiglumide.

To evaluate the physiological role of cholecystokinin (CCK) in humans, we studied the influence of the specific CCK receptor antagonist loxiglumide (CR 1505) on gallbladder contraction, pancreatic enzyme output, plasma CCK concentrations, mouth-to-cecum transit time (MCTT), stool weight, and fecal fat excretion. Infusion of CCK-8, producing CCK plasma levels of 10-12 pmol/l, decreased gallbladder volume to 21% of the initial volume (P less than 0.01) and increased bilirubin output 8- to 10-fold and pancreatic enzyme secretion 2- to 4-fold. Infusion of loxiglumide (10 mg.kg-1.h-1 iv) abolished CCK-8-stimulated enzyme and bilirubin output. Basal gallbladder volume increased 68% during loxiglumide infusion (P less than 0.001) and 137% (P less than 0.001) after 7 days of oral loxiglumide treatment (3 x 1.6 g/day). Gallbladder contraction and bilirubin output in response to the intraduodenal instillation of a liquid meal (382 kcal) was completely inhibited by loxiglumide; gallbladder volume even increased 45% postprandially during loxiglumide infusion (P less than 0.02) and 145% after long-term loxiglumide treatment (P less than 0.001). Meal-stimulated pancreatic enzyme output was diminished 46-53% after acute and 25-29% after chronic administration of loxiglumide. Meal-stimulated integrated plasma CCK-immunoreactive (CCK-ir) concentrations, determined by RIA, were 3.2-fold higher during loxiglumide infusion (P less than 0.02); plateau CCK levels were markedly elevated (10.1 +/- 1.4 vs. 3.7 +/- 0.5 pM). Plasma CCK-like bioactivity, measured by a sensitive bioassay, was identical to CCK-ir levels in the absence of loxiglumide; in the presence of loxiglumide, no circulating CCK-like bioactivity was detectable, indicating complete inhibition of plasma CCK. MCTT was augmented 24% (P less than 0.05). Oral treatment with loxiglumide increased stool weight 72% (P less than 0.01) and fecal fat excretion 186% (P less than 0.001). In conclusion, 1) meal-induced gallbladder contraction and fasting tone are primarily controlled by CCK; 2) the contribution of CCK to the intestinal phase of postprandial pancreatic enzyme secretion is 40-50%; 3) GI motility and absorption are partially controlled by CCK; and 4) postprandial CCK secretion is substantially augmented by loxiglumide via an unknown mechanism.

Dose equivalence of midazolam and triazolam. A psychometric study based on flicker sensitivity, reaction time and digit symbol substitution test.

The pharmacodynamic potency of oral midazolam, a new ultrashort-acting hypnotic benzodiazepine, has been evaluated relative to a standard dose of triazolam, a well established oral benzodiazepine with a similar pharmacological profile. In a balanced design, double-blind cross-over study 6 healthy volunteers received 3.75, 7.5, and 15 mg midazolam and 0.25 mg triazolam orally, at 8 a.m., at weekly intervals. Drug effects were repeatedly measured over 8 h by a new psychometric method, the threshold amplitude for perception of flickering light (TPF) assessed at 5 and 30 Hz. Auditory reaction time, digit-symbol substitution test (DSST), and self-rating by subjects served as reference standards. Median midazolam doses equivalent to 0.25 mg triazolam, interpolated on dose-response curves for peak effects, were 5.2 mg (TPF 30 Hz), 6.4 mg (TPF 5 Hz), 6.5 mg (DSST), and 7.4 mg (reaction time), respectively. Alternative methods of data analysis gave similar results. Introduction of TPF as a highly reproducible and sensitive measure of the effect of benzodiazepines on the CNS offers new opportunities to compare the relative potencies of different benzodiazepines in man. Since clinical experience has shown 0.25 mg triazolam to be safe and effective, it is concluded that the corresponding single oral dose of midazolam is between 5 and 8 mg.

Ciclosporin concentration in the rabbit aqueous humor and cornea following subconjunctival administration. Importance of anatomical site of injection.

The model compound lidocaine was used in the rabbit to investigate different sites of subconjunctival injection for the achievement of reproducible drug concentrations in the aqueous humor. Only epibulbar injections were satisfactory, but not parabulbar or injections under the lower fornix. After epibulbar administration of 0.8 ml 5% ciclosporin, median concentrations in the aqueous humor were 360, 700 and 200 ng/ml after 2, 8, and 24 h, respectively. Corresponding levels in the cornea were 32, 27, and 12 ng/ml. It appears that drug concentrations resulting from epibulbar injections may be therapeutically useful.

Demonstration of immunoreactive calcitonin in sera and tissues of lung cancer patients.

In sera of 194 patients with lung carcinoma, calcitonin was estimated by radioimmunoassay with an antibody against human calcitonin. Increased levels of calcitonin-immunoreactive protein were found in 57% of the patients with small cell carcinoma, in 10% of the patients with squamous carcinoma and in only 2 patients with large cell carcinoma. In patients with small cell carcinoma, serial determinations of calcitonin were accomplished during therapy. Significantly decreased calcitonin levels were found in patients who responded to therapy with cytostatics and X-ray. Increased calcitonin levels were measured from 1 to 2 months before clinical symptoms of a relapse were detectable. Investigations on the biochemical nature of this calcitonin-immunoreactive protein were made on both serum of lung cancer patients and tumor tissue. Evidence for the production of calcitonin-immunoreactive protein directly by the tumor was given by immune histology and by determinations of calcitonin in tumor tissue. Three protein fractions, which were immunoreactive with anti-human calcitonin, with molecular weights of about 100,000, 48,000 and 20,000, were separated by gel filtration. The two higher molecular weight fractions were degraded to molecular weights of about 17,000 and about 3400--the molecular weight of physiological calcitonin--by incubation with sodium dodecyl sulphate under reducing conditions. These results led to the conclusion that it may be possible to characterize a tumor-specific calcitonin precursor molecule; in addition to its use in monitoring therapy it may be useful in the differential diagnosis of small cell carcinoma.