Emerging drugs for postoperative ileus

Postoperative ileus (POI) is an impairment of coordinated gastrointestinal (GI) motility that develops as a consequence of abdominal surgery and is a major factor contributing to patient morbidity and prolonged hospitalization. Although the origin and cause of POI are poorly understood, it is known that abnormal GI motility associated with delayed gastric emptying and intestinal transit is a major factor leading to abdominal bloating, vomiting and lack of defecation. Furthermore, opioid drugs such as morphine, used for the management of postoperative pain, cause inhibition of bowel transit. Proposed mechanisms of POI include the stimulation of neuronal responses, such as excitation of afferent neurons and activation of noradrenergic, non-adrenergic and non-cholinergic neuronal pathways, as well as the induction of an intestinal inflammatory response. The development of new pharmacological strategies to prevent or reduce the frequency of POI is very important as existing approaches do not offer relief for most patients. This review describes emerging therapeutics that may advance the care of patients with POI.     

A randomized, placebo-controlled, crossover, double-blind trial of the NK1 receptor antagonist aprepitant on gastrointestinal motor function in healthy humans

Background  Little is known about the role of tachykinins on human gastrointestinal motility and no data exist on the possible effect of an NK1 receptor antagonist.
Aim  To examine the effect of an antiemetic dose of the selective NK1 receptor antagonist aprepitant on gastrointestinal propulsion in healthy humans.
Methods  Twelve healthy volunteers participated in a crossover, double-blind study. In random order, each volunteer had a 125-mg capsule of aprepitant or placebo on day 1 followed by an 80-mg capsule of aprepitant or placebo on days 2–5. Gamma camera imaging was used to measure gastric emptying, small intestinal transit and colonic transit of a radiolabelled, 1600-kJ mixed liquid and solid meal ingested on day 2.
Results  Aprepitant did not change gastric retention at 15 min, gastric half emptying time, gastric mean transit time, time to small intestinal transit of 10%, small intestinal mean transit time or colonic geometric centre after 24, 48 and 72 h.
Conclusion  A 125-mg capsule of aprepitant followed by an 80-mg capsule of aprepitant each of the next 2–5 days did not induce major changes in the propulsive function of the gastrointestinal tract in the small number of healthy volunteers investigated.     

The Effect of the Cholecystokinin Antagonist Devazepide (L364718) on the Ileal Brake Mechanism in the Rat

Abstract— Studies were carried out on 28 male adult rats to investigate whether the selective cholecystokinin-receptor antagonist devazepide influences gastrointestinal transit under control conditions and when it is delayed by ileal infusion of lipid. Stomach-to-caecum transit time of the head of the test meal was measured using environmental hydrogen analysis and the distribution of the meal was assessed using the radiolabeled meal technique. Oral administration of devazepide (4 mg kg^?1) had no significant effect on transit time of the head of the baked bean test meal under control conditions, but significantly reversed the delay in transit time induced by ileal infusion of lipid (P < 0·01). Studying the distribution of the meal showed that Intralipid delayed transit time by delaying both gastric emptying (P < 0·01) and small bowel transit (P < 0·05). Devazepide did not alter the control distribution of the meal during ileal saline infusion, but during ileal infusion of lipid, devazepide further delayed gastric emptying (P < 0·01); the geometric centre of the meal was situated more proximally in the gastrointestinal tract (P < 0·05), but there was more of the meal in the colon (P < 0·01). The latter is compatible with the early rise in environmental hydrogen during devazepide administration and ileal lipid infusion and suggests that peripheral cholecystokinin receptors may modulate or mediate the delay in small bowel transit induced by ileal lipid. However, the data also suggest that mechanisms other than those involving cholecystokinin play a dominant role in the regulation of postprandial and lipid-delayed gastric emptying of a meal.     

The pharmacological effects of Daikenchuto, a traditional herbal medicine, on delayed gastrointestinal transit in rat postoperative ileus

The effect of Daikenchuto, a traditional herbal medicine, on gastrointestinal hypoperistalsis in postoperative ileus (POI) was investigated. POI was induced by laparotomy with manipulation of the gastrointestine under anesthesia, and gastrointestinal transit was calculated by migration of Evans blue. Daikenchuto (270 - 2,700 mg/kg, p.o.) dose-dependently improved the delayed gastrointestinal transit in POI. This effect of Daikenchuto was partially inhibited by SB204070 (1 mg/kg, s.c.), a 5-hydroxytriptamine(4) (5-HT(4))-receptor antagonist and completely abolished by atropine (1 mg/kg, s.c.), a muscarine-receptor antagonist. Among the constituents of Daikenchuto, the medical herb zanthoxylum fruit (60 mg/kg, p.o.) and maltose syrup (2,400 mg/kg, p.o.) significantly ameliorated the delayed gastrointestinal transit, but ginseng and processed ginger did not affect the gastrointestinal transit in the rat POI. The improvement induced by zanthoxylum fruit was also inhibited by atropine or SB204070. In addition, the high osmotic pressure of the maltose syrup (2400 mg/10 mL per kg) was related to the improvement of delayed gastrointestinal transit. These results demonstrated that Daikenchuto ameliorates postoperative hypoperistalsis via cholinergic nerves and 5-HT(4) receptors and that osmotic pressure also may be involved in this action. Moreover, zanthoxylum fruit and maltose syrup were crucial medical herbs contributing to the ability of Daikenchuto.     

The relationship between gastrointestinal transit and motility in dogs with postoperative ileus

We investigated the relationship between gastrointestinal (GI) transit and motility during postoperative ileus in dogs undergoing a single laparotomy. We combined X-ray radiography for a GI transit study with chronically implanted force transducers (FTs) for a GI motility study. Radio-opaque markers made of polyethylene and steel wires or barium sulfate were used to examine solid substance transit or liquid substance transit. For a while after the end of the operation, postoperative ileus was observed, with weak irregular contractions of the GI tract. Transmission of the contractions to the lower GI tract was then observed. The start point of interdigestive migrating contraction (IMC)-like motility was observed in the order of small intestine (I-IMC), duodenum (D-IMC), and stomach (G-IMC), and IMC proceeded gradually after the operation. The gastric emptying time of a solid marker was 73.6 +/- 2.3 h (n = 5), and depended on the time of first occurrence of G-IMC (r = 0.674, p = 0.006). The gastric emptying of the liquid marker was finished before the time of the first occurrence of G-IMC, and its small intestinal transit time correlated with the time of the first occurrence of G-IMC (r = 0.888, p = 0.018). Using combined X-ray radiography and FTs we found that recovery from postoperative ileus was aided by GI motility in which contractions were transmitted from the stomach to the lower GI tract, like IMC.     

Gastrointestinal transit of pellets of differing size and density

The gastrointestinal transit of four multiple unit pellet dosage forms of two sizes 0.5 and 4.75 mm and two densities 1.5 and 2.6 g cm⁻³ was examined by gamma scintigraphy in eight healthy fasted subjects. The pellets were prepared by the processes of extrusion and spheronisation and radiolabelled with ^99mTc or ^IIIIn. Small pellets of normal and high density were examined on one occasion and large pellets of normal and high density on another. The small and large pellet data from each administration were analysed separately, and then pooled to determine the overall effects of size and density on gastrointestinal transit. A distinct lag phase before gastric emptying commenced was observed for all pellets. The onset of emptying was not affected by size or density. Thereafter gastrointestinal transit did appear to be prolonged with an increase in density. This effect was more clearly demonstrated by the smaller pellets. Small pellet data and the pooled data indicated that an increase in density delayed gastric emptying and prolonged small intestinal residence time (p < 0.05). The large pellet data alone, also indicated that the increase in density caused a delay in gastric emptying (p < 0.05) but the prolongation of small intestinal residence time was not significant. Gastric emptying of the pellets was not affected by their size, although small intestinal residence time was prolonged by the large pellets (p < 0.05). These results and those previously reported by the authors (Clarke et al., Int. J. Pharm., (1993 in press) suggest that there may be a threshold density, of the order of 2.4–2.6 g cm⁻³, above which gastric emptying is prolonged. The delayed gastric emptying and prolonged small intestinal residence time have important implications for the rational design of sustained release oral dosage forms.     

The Effect of In Vivo Dissolution,Gastric Emptying Rate,and Intestinal Transit Time on the Peak Concentration and Area-Under-the-Curve of Drugs with Different Gastrointestinal Permeabilities

Purpose. To theoretically investigate the impact of gastric emptying half-time, intestinal transit time and the time for 85% in vivo dissolution on the peak concentration and area-under-the curve of model drugs. Methods. Simulations were performed using mathematical models of gastrointestinal physiology and pharmacokinetics of model drugs with different gastrointestinal permeability. They were used to investigate the effect of different permutations of gastric emptying times, intestinal transit times, dissolution rates and effective permeabilities on the maximum plasma drug concentration and the area-under-the-curve of immediate release tablets relative to an oral solution (i.e., Cmax_tablet/ Cmax_solution and AUC_tablet/AUC_solution). Results. The higher the permeability of the drug, the more sensitive the Cmax ratio is to dissolution rate and gastric emptying rate. As the intestinal transit time becomes more rapid, the sensitivity to T85% dissolution time and gastric emptying half-time increases. There is less dependence for the AUC ratio on the gastric emptying time and dissolution rate. Conclusions. Under the assumptions of the models, the criterion of 85% dissolution in 15 minutes (T85%) for classifying a rapidly dissolving drug product is relatively conservative since the Cmax ratio exceeded 0.8 for a T85% dissolution time of one hour and a gastric emptying half-time faster than 0.2 hour over a wide range of permeabilities.     

Involvement of cholecystokinin receptor in the inhibition of gastrointestinal motility by oxytocin in ovariectomized rats

The effects of oxytocin on gastric emptying, gastrointestinal transit, and plasma levels of cholecystokinin (CCK) were studied in ovariectomized rats. Gastrointestinal motility was assessed in rats 15 min after intragastric instillation of a test meal containing charcoal and Na₂⁵¹CrO₄. Gastric emptying was determined by measuring the amount of radiolabeled chromium contained in the small intestine as a percentage of the initial amount received. Gastrointestinal transit was evaluated by calculating the geometric center of distribution of the radiolabeled marker. Blood samples were collected for CCK radioimmunoassay. After administration of oxytocin (0.2–0.8 mg/kg), gastric emptying and gastrointestinal transit were inhibited, whereas plasma concentration of CCK was increased in a dose-dependent manner. Atosiban, an oxytocin receptor antagonist, effectively attenuated the oxytocin-induced inhibition of gastric emptying and gastrointestinal transit. However, administration of atosiban alone had no effect on gastric emptying and gastrointestinal transit. The selective CCK₁ receptor antagonists, devazepide and lorglumide, effectively attenuated the oxytocin-induced inhibition of gastric emptying and gastrointestinal transit. L-365, 260, a selective CCK₂ receptor antagonist, did not alter the oxytocin-induced inhibition of gastric emptying and gastrointestinal transit. These results suggest that oxytocin inhibits gastric emptying and gastrointestinal transit in ovariectomized rats via a mechanism involving the stimulation of CCK release and CCK₁ receptor activation.     

The assessment of regional gut transit times in healthy controls and patients with gastroparesis using wireless motility technology

Background Wireless pH and pressure motility capsule (wireless motility capsule) technology provides a method to assess regional gastrointestinal transit times. Aims To analyse data from a multi‐centre study of gastroparetic patients and healthy controls and to compare regional transit times measured by wireless motility capsule in healthy controls and gastroparetics (GP). Methods A total of 66 healthy controls and 34 patients with GP (15 diabetic and 19 idiopathic) swallowed wireless motility capsule together with standardized meal (255 kcal). Gastric emptying time (GET), small bowel transit time (SBTT), colon transit time (CTT) and whole gut transit time (WGTT) were calculated using the wireless motility capsule. Results Gastric emptying time, CTT and WGTT but not SBTT were significantly longer in GP than in controls. Eighteen percent of gastroparetic patients had delayed WGTT. Both diabetic and idiopathic aetiologies of gastroparetics had significantly slower WGTT (P < 0.0001) in addition to significantly slower GET than healthy controls. Diabetic gastroparetics additionally had significantly slower CTT than healthy controls (P = 0.0054). Conclusions In addition to assessing gastric emptying, regional transit times can be measured using wireless motility capsule. The prolongation of CTT in gastroparetic patients indicates that dysmotility beyond the stomach in GP is present, and it could be contributing to symptom presentation. Aliment Pharmacol Ther 31 , 313–322     

Effect of a novel 5-HT3 receptor agonist MKC-733 on upper gastrointestinal motility in humans

BACKGROUND: Although 5-HT3 antagonists have been used to treat chemotherapy-induced emesis and diarrhoea-predominant irritable bowel syndrome, the effects of 5-HT3 agonists in humans are unknown. AIM: To determine the effect of MKC-733, a selective 5-HT3 receptor agonist, on upper gastrointestinal motility. METHODS: Oral MKC-733 (0.2, 1 and 4 mg) was compared with placebo in three randomized, double-blind, cross-over studies in healthy males. Antroduodenal manometry was recorded for 8 h during fasting and 3 h post-prandially (n = 12). Gastric emptying and small intestinal transit were determined by gamma-scintigraphy (n = 16). Gastric emptying, accommodation and antral motility were determined by echoplanar magnetic resonance imaging (n = 12). RESULTS: MKC-733 (4 mg) increased the number of migrating motor complexes recorded in the antrum and duodenum (P < 0.001), but had no effect on post-prandial motility. MKC-733 delayed scintigraphically assessed liquid gastric emptying (P = 0.005) and accelerated small intestinal transit (P = 0.038). Echoplanar magnetic resonance imaging confirmed the delayed gastric emptying (P < 0.001) and demonstrated a significant increase in cross-sectional area of the proximal stomach (P < 0.01). CONCLUSIONS: MKC-733 delays liquid gastric emptying in association with relaxation of the proximal stomach, stimulates fasting antroduodenal migrating motor complex activity and accelerates small intestinal transit.     

Performance characteristics of scintigraphic transit measurements for studies of experimental therapies

BACKGROUND: The intra- and inter-individual reproducibility of gastrointestinal and colonic transit tests require full characterization. AIMS: (i) To characterize the normal values and reproducibility effects of age and gender on the scintigraphic transit of solids in health. (ii) To compare scintigraphic and radio-opaque marker measurements of colonic transit. (iii) To estimate demonstrable effect sizes for different transit end-points based on observed variations. METHODS: A scintigraphic gastrointestinal and colonic transit study and the mean colonic transit time were measured using radio-opaque markers in 37 healthy volunteers; 21 subjects had a repeat scintigraphic test 3 weeks later. RESULTS: Gastric emptying at 4 h was highly reproducible (coefficient of variation, 4%) on repeat testing. The colonic measurement varied by more than 1 geometric centre unit in 37% of subjects at 24 h and in 26% of subjects at 48 h. There were no age- or gender-related differences in transit. Effect sizes demonstrable with 14 subjects per group were in the range previously shown to be clinically relevant: 25% change in gastric emptying at 4 h; 1.5 geometric centre unit change in colonic transit at 48 h. CONCLUSIONS: These data demonstrate the reproducibility and performance to be expected of transit measurements and are essential for designing studies in experimental therapeutics.     

厚朴丸对小鼠胃肠活动的影响

目的:观察厚朴丸对小鼠胃排空和小肠推进运动的影响.方法:利用胃复安和阿托品造成小鼠胃排空亢进和胃排空抑制模型,利用新斯的明和肾上腺素造成小鼠小肠推进亢进和小肠推进抑制模型,观察厚朴丸对正常、亢进及抑制状态下小鼠胃肠活动的影响.结果:厚朴丸抑制正常小鼠胃排空和胃复安所致小鼠胃排空加快,能加强阿托品所致小鼠胃排空的抑制作用;对正常小鼠小肠推进和新斯的明所致小鼠小肠推进亢进也有抑制作用,但对肾上腺素所致小鼠小肠推进抑制无明显影响.结论:厚朴丸具有抑制正常和亢进状态的小鼠胃排空和小肠推进的作用,与临床用于止泻相符合.     

Prazosin inhibits small intestinal transit in the rat

Gastric emptying, small intestinal transit, and colonic transit were measured in fasted rats preimplanted with either duodenal or colonic cannulae. At the doses stated, prazosin (given subcutaneously) had no effect on gastric emptying or colonic transit, whereas small intestinal transit was significantly delayed.     

Stimulatory effect of N-[4-[2-(dimethylamino)-ethoxy] benzyl]-3,4-dimethoxybenzamide hydrochloride (HSR-803) on normal and delayed gastrointestinal propulsion

To estimate the effect of a new gastroprokinetic agent, N-[4-[2-(dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide hydrochloride (HSR-803), on non-ulcer dyspepsia, the influence of HSR-803 on gastrointestinal propulsion was assayed in dogs, rats and mice in comparison with some gastroprokinetic agents. HSR-803 (30 mg/kg, p.o.) significantly enhanced gastric emptying in dogs, and it significantly improved the delayed gastric emptying induced by dopamine (0.4 mg/kg, i.p.) and morphine (1 mg/kg, s.c.) in rats. Metoclopramide (30 mg/kg, p.o.) also significantly restored the dopamine-induced delay, but at a dose of 10 mg/kg, p.o., it enhanced the morphine-induced delay in gastric emptying in rats. HSR-803 (10-100 mg/kg, p.o.) increased small intestinal transit in mice in a dose-dependent manner, and the effect was abolished by atropine (0.3 mg/kg, i.p.). Metoclopramide also increased small intestinal transit, but domperidone and cisapride had no effect. In delayed small intestinal transit in mice, HSR-803 (10-100 mg/kg, p.o.) improved the morphine (0.3 mg/kg, s.c.)-induced delay in a dose-dependent manner. In conclusion, because of the promotion of normal and delayed gastrointestinal propulsion, HSR-803 seems to be a promising gastroprokinetic agent for the treatment of non-ulcer dyspepsia. The action of HSR-803 is likely to be exerted through cholinergic stimulation.     

Action of T-2 toxin on gastrointestinal transit in mice: protective effect of an argillaceous compound

Using sodium [51Cr]chromate as radiolabeled marker, gastrointestinal transit of a milk test meal was determined in mice receiving for 4 days T-2 toxin (1 mg/kg per day per os) alone or with a clay, smectite (2 g/kg per day), given according to four different procedures. Gastric emptying and small intestinal transit were significantly accelerated after the 1st T-2 administration and during the 4 days of treatment. When smectite was given together with the toxin with or without pretreatment by smectite alone for 2 days, the T-2 induced disturbances in gastrointestinal transit remained unchanged. A pretreatment by smectite for 4 days abolished the T-2 induced acceleration of gastric emptying but not of small intestinal transit. When T-2 was incubated with smectite for 24 h before oral administration, gastric emptying and small intestinal transit were not significantly accelerated.     

Antipropulsive effects of central and peripheral morphine in the rat gastrointestinal tract

The antipropulsive effects of centrally or peripherally administered morphine have been examined at three levels of the rat gastrointestinal tract. Adult male rats were anaesthetized with pentobarbitone (50 mg kg-1 i.p.) and were implanted with an intraluminal catheter in either the proximal duodenum or mid-jejunum. Other animals were also implanted with a cannula in the right lateral cerebral ventricle. Gastric emptying and transit were determined selectively by measuring the progression of a radioactive chromium (CR-51) solution, given intragastrically for tests of gastric emptying or instilled into the proximal or distal intestinal catheter for determination of intestinal transit, 30 min after administration of morphine or saline given either subcutaneously (s.c.) or intracerebroventricularly (i.c.v.). Morphine given either s.c. (5 mg kg-1) or i.c.v. (30 micrograms, total dose) significantly inhibited gastric emptying and transit through bulk portions of the small intestine indicating that by either route it inhibits propulsion at all three levels of the gastrointestinal tract.     

Omeprazole-induced slowing of gastrointestinal transit in mice can be countered with tegaserod

Omeprazole, besides suppressing gastric acid, causes delayed gastric emptying, which may be associated with aggravated dyspeptic symptoms. Effects of omeprazole on small intestinal transit are unknown. In this study, we evaluated in mice if (a) omeprazole affects transit of a meal through the stomach and small intestine and (b) co-treatment with the promotility agent, tegaserod, can prevent the slowing effect of omeprazole. Omeprazole (40-150 mg/kg, i.p. once daily for 5 days) delayed gastric emptying of the meal in a dose-related manner. Small intestinal transit was then evaluated at the lowest dose of omeprazole (40 mg/kg) that did not retard gastric emptying. Such transit was significantly delayed after this dose of omeprazole compared with vehicle-treated controls. When tegaserod (0.10 mg/kg) was administered concomitantly with the omeprazole, small intestinal transit of the meal was not slowed and was not different from controls. These results show that omeprazole reduces aboral transit of luminal contents through the stomach and small bowel of mice and that this delay is reversed by tegaserod.     

Effect of centrally administered C75, a fatty acid synthase inhibitor, on gastric emptying and gastrointestinal transit in mice

The central or systemic administration of 3-carboxy-4-octyl-2-methylenebutyrolactone (C75), a synthetic inhibitor of fatty acid synthase (FAS), causes anorexia and profound weight loss in rodents. The amount of food intake and gastrointestinal mobility are closely related. In this study, an attempt has been made to investigate the effects and mechanisms of C75 on gastric emptying and gastrointestinal transit after intracerebroventricular (i.c.v.) injection in mice. Our data showed that C75 (1, 5, 10 microg/mouse) dose-dependently delayed gastric emptying and gastrointestinal transit in fasted mice. 10 microg C75 delayed gastric emptying by about 21.4% and reduced gastrointestinal transit by about 31.0% compared with vehicle control group. Administration (i.c.v.) of 5-(tetradecyloxy)-2-furoic acid (TOFA, an acetyl-CoA carboxylase (ACC) inhibitor) or ghrelin attenuated the delayed gastrointestinal mobility effect induced by 10 microg C75. Taken together, C75 is able to decrease gastrointestinal mobility and it seems possible that malonyl-CoA and ghrelin might play an intermediary role in these processes.     

The effect of ether and pentobarbitone sodium on gastrointestinal function in the intact rat

The effect of ether and pentobarbitone anaesthesia on gastrointestinal motility and absorption has been studied by measuring simultaneously gastric emptying, small intestinal transit and intestinal absorption of glucose and iodide in intact rats. Both gastric emptying and intestinal transit are very slow under ether anaesthesia, but with pentobarbitone there is no significant delay. The absorption of glucose by the small intestine is significantly impaired by ether but not by pentobarbitone, and a tracer dose of iodide is absorbed normally under both forms of anaesthesia.     

Variation in Gastrointestinal Transit of Pharmaceutical Dosage Forms in Healthy Subjects

The variability in the gastrointestinal transit of a multiple-unit and single-unit dosage form was investigated following a light breakfast in six, healthy, male volunteers after repeated weekly administration. The dosage forms were labeled with gamma-emitting radionuclides and the transit of the formulations was monitored on 4 separate study days using the technique of dual-isotope gamma scintigraphy. Gastric emptying times and small intestinal transit times were calculated and compared statistically within and between subjects using the standard deviation and coefficient of variance. The variability in gastric emptying of single- and multiple-unit systems was large; the intrasubject variation being less than the intersubject. There was less variation in small intestinal transit times for the single- and multiple-unit formulations than in gastric emptying, intrasubject variation again being less than intersubject variation.