Impaired transit of chyme in chronic intestinal pseudoobstruction. Correction by cisapride

Chronic intestinal pseudoobstruction is a clinical syndrome whose pathophysiology, objective diagnosis, and treatment are poorly understood. We investigated 8 patients with this syndrome in whom intestinal dysmotility was established manometrically by two or more of the following criteria: abnormal configuration or propagation of interdigestive motor complexes, sustained incoordinate pressure activity, non-propagated bursts of phasic pressure activity, and failure of a solid-liquid meal to induce a fed pattern. To establish the functional impairment and region of the gut primarily affected by the disease, we quantified radio-scintigraphically the gastrointestinal transit of the solid (131I-fiber) and liquid (99 mTc-DTPA) components of a meal. Our techniques allowed us to quantify separately gastric emptying and pylorus-to-cecum transit. Furthermore, we evaluated the effects of a new prokinetic agent, cisapride. Gastric emptying times in pseudoobstruction were not significantly delayed; however, transit times through the small bowel (t1/2) were markedly prolonged [solids, 235 +/- 43 min (mean +/- SEM) vs. 138 +/- 25 controls, p less than 0.05; liquids, 310 +/- 67 vs. 181 +/- 28 controls, p = 0.07]. Cisapride was effective in reducing the delayed intestinal transit time to within the normal range (delta solids = -115 +/- 25 min; delta liquids = -146 +/- 71 min; p less than 0.05 for both). These studies suggest that intestinal dysmotility in this group of patients with pseudoobstruction was associated with delayed small bowel transit of radiolabeled solid and liquid components of chyme. Cisapride can restore to normal the delayed transit, indicating that it may potentially correct the impaired propulsive activity in the small bowel of these patients.     

Effect of dietary fiber on gastrointestinal motility and jejunal transit time in dogs

Strain gauge recordings of the motility of the antrum, duodenum, and jejunum were made in 10 dogs receiving a daily meal of canned food. Addition of 30 g of either wheat bran, cellulose, or guar gum increased the duration of the postprandial pattern of motility by 41-54% in the duodenum. Only cellulose and gum caused increases in the duration of the postprandial pattern of motility in the jejunum. The normal postprandial pattern of duodenojejunal contractions consisted of bursts of 4-10 rhythmic contractions. When bran or cellulose were added, the bursts were prolonged (12-15 contractions per burst) with 4-15 min intervals between bursts. In contrast, when gum was added, contractions occurred continuously at a rate of 7-8/min, but their amplitude was one-half that seen with the other fibers. The increased number of low amplitude contractions when gum was added caused the postprandial motility index to double. There was no change in the motility index when cellulose was added. Guar gum also increased the frequency of antral contractions by 129%, while bran and cellulose had no effect. Jejunal transit time and flow of digesta were measured in four dogs 2 h after the meal. Addition of bran or gum increased the transit time by 28% and 51%, respectively, but cellulose caused a 900% increase in transit time associated with a 50% reduction in the flow of digesta. Addition of different fibers causes different alterations in postprandial motility. Jejunal transit of digesta appears unrelated to the pattern of contractions.     

Postprandial patterns of canine jejunal motility and transit of luminal content

The effects of different nutrient meals and a noncaloric viscous cellulose meal (control) on the motor activity of the canine jejunum were studied. Contraction patterns were detected through six closely spaced, strain-gauge transducers and were analyzed by a computer. Luminal transit was assessed videofluoroscopically. Control meals moved rapidly (1.9 cm/s) along the jejunum. This was achieved by contractions that occurred at a high frequency (12.8 cpm) and propagated over long distances (9.9 cm). In contrast, the transit rates of the nutrient meals were considerably slower (0.5-1.0 cm/s), the frequency of contractions (5.0-8.9 cpm) and the length of spread of contraction waves (2.6-4.8 cm) were decreased, and the incidence of stationary contractions occurring individually or in clusters was increased. A mathematical model incorporating frequency of contractions and the length of their propagation was used to predict the transit of jejunal contents. The results of correlation tests and of the mathematical model revealed that the length of spread of contraction waves was the most important factor that influenced transit.     

Human gastric and jejunal transit and motility after Roux gastrojejunostomy.

Upper gut transit and motility among 10 symptomatic and 9 asymptomatic patients with Roux gastrectomy were compared with those among 10 healthy, unoperated controls. Gastric emptying of solids and Roux limb and small intestinal transit of liquids were assessed scintigraphically. Motor patterns in the Roux limb or healthy jejunum were recorded manometrically. Whereas gastric emptying was sometimes faster and sometimes unchanged after Roux gastrectomy compared with controls, Roux limb transit in patients was consistently slower than jejunal transit in controls. Postprandially, the Roux limb showed decreased overall motility, fewer clustered waves, and less aboral migration of clustered waves than the healthy jejunum. Symptomatic Roux patients had jejunal transit and motor patterns similar to those of asymptomatic patients. Nonetheless, reflux from Roux limb to gastric remnant occurred in 4 of 10 symptomatic patients but in none of the asymptomatic patients. In conclusion, stasis and dysmotility are present in the Roux limb after Roux gastrectomy and Roux-gastric reflux can occur. Other factors, however, must have a role in determining whether symptoms appear.     

Effect of jejunal infusion of bile acids on small bowel transit and fasting jejunal motility in man.

The effect of jejunal infusion of glycochenodeoxycholic acid and glycocholic acid on small bowel transit time, fasting jejunal motility and serum bile acid concentrations was investigated in groups of five to six healthy subjects. Glycochenodeoxycholic acid at a concentration of 15 mmol/l (total amount: 5 mmol) and glycocholic acid 15 mmol/l (total amount: 5 mmol), both with lecithin 2.5 mmol/l, delayed (p less than 0.02) small bowel transit when compared with a bile acid free infusion [158.3 (12.5) min v 111.7 (17.6) min and 103.3 (21.8) min v 70.0 (14.9) min], inhibited (p less than 0.01 and p less than 0.05 respectively) the percentage duration of pressure activity of phase 2 [13.1 (1.8)% v 28.1 (3.4)% and 29.2 (5.5)% v 34.9 (3.9)%], but did not change duration of migrating motor complex, or of its phases. Glycochenodeoxycholic acid 10 mmol/l (total amount: 3.3 mmol), either with or without lecithin, did not delay small bowel transit significantly [145.0 (13.2) min v 115.0 (19.5) and 90.0 (11.7) min v 84.0 (8.3)]. When bile acids were infused, serum bile acid curves were similar to those obtained after a liquid meal and the peak serum bile acid concentration occurred 33.7 (6.6) min before (p less than 0.001) completion of small bowel transit. These observations suggest a role for endogenous bile acids in the regulation of small gut motility.     

Role of vagal dysfunction in motility and transit disorders of jejunal roux limb after roux-en-Y gastrojejunostomy

After a Roux-en-Y gastrojejunostomy patients frequently complain about abdominal pain, fullness, nausea and vomiting, ie, the Roux-en-Y syndrome. Stasis in the Roux limb due to disordered motility is known to be a cause of these complaints. The aim of the present study was to determine whether vagal denervation contributes to the development of motility disturbances and stasis in the Roux limb. Forty-seven patients with a Roux-en-Y gastrojejunostomy after partial gastrectomy were studied. A truncal vagotomy had been performed in 26 of these 47 patients. Transit through the Roux limb was evaluated by radionuclide studies, motility in the Roux limb was studied by manometry, and vagal function was tested by measuring the pancreatic polypeptide response to an insulin-induced hypoglycemia (PP test). On the basis of the PP test patients were classified as having (1) normal, (2) moderately impaired, and (3) severely impaired vagal function. The PP test showed that two of the 26 patients subjected to vagotomy had a moderately impaired vagal function, the other 24 all had a severely impaired vagal function. In the patients not subjected to a vagotomy, vagal function was disturbed in 11 of the 21 patients. Motility disturbances were not observed more frequently in patients with either moderately or severely impaired vagal function than in patients with normal vagal function. Stasis in the Roux limb was seen even more frequently in patients with a normal vagal function than in patients with a severely impaired vagal function. The results of this study indicate that vagal denervation of the Roux limb is not the cause of motility and transit disorders in the Roux limb.This work was supported by the Jan Kornelis de Cock-Stichting.     

Effects of cisapride on postcibal jejunal motor activity

In the jejunum of fasting humans, cisapride induces a phase 2-like, highly propagative motor pattern. This study investigated cisapride's effects on the fed pattern of the jejunum. Starting 5 min after a phase 3 of the migrating motor complex, 18 healthy men received 5 or 10 mg cisapride or placebo orally in random double-blind fashion and ingested meals containing 1000 and 4200 kJ, respectively. Jejunal pressures were recorded pneumohydraulically with five catheter orifices 10–30 cm aborad the ligament of Treitz. After the 4200-kJ meal, total number and number of propagated contractions as well as area under the curve increased significantly more than after 1000 kJ. Following the 1000-kJ but not the 4200-kJ meal, 10 mg cisapride increased total number of contractions, number of propagated contractions, mean amplitude, and area under curve significantly more than placebo. Fed-pattern duration increased with the meal's caloric content but was not influenced systematically by cisapride. In conclusion, cisapride stimulates jejunal motor activity and induces a propagative pattern after a 1000-kJ but not after a 4200-kJ meal, suggesting that it can produce no further stimulation when motor activity is near maximally enhanced already.     

Cisapride stimulates propulsive motility patterns in human jejunum

The effects of cisapride on upper gut motility were studied in seven healthy volunteers by means of a novel intraluminal electromyographic technique in a placebo-controlled study. In the interdigestive state, cisapride (10 mg intravenous bolus injection) markedly increased the number of spike bursts. The most obvious effect was observed during the first 5-min period when a nonmigrating phase-3-like activity (stationary phase 3) occurred, which lasted for 2.6±0.4 min. This initial pattern was followed by an intense phase 2 activity, characterized by a 10-fold increase in the number of groups of repetitive spike bursts and a sixfold increase in the number of ultrarapid single propagated spike bursts (ultrarapid peristaltic rushes). Cisapride induces in the human upper gut a remarkable pattern of aborally propagated (peristaltic) contractions, which are very likely responsible for the active propulsion of intestinal contents in the interdigestive state.     

Effects of cisapride on gastrointestinal transit in healthy humans

It was the aim of this study to assess the effects of cisapride on gastrointestinal transit of solids in healthy humans. Twelve men received cisapride 10 mg or placebo orally four times a day in random, double-blind, crossover fashion. Transit measurements were performed with a new gamma camera technique. Cisapride reduced mean gastric emptying time of 99mTc-labeled cellulose fiber [0.77 (0.69-1.12) hr [median (range)] vs 0.98 (0.63-1.95) hr; P less than 0.05] and 1- to 2-mm 111In-labeled plastic particles [1.08 (0.50-1.42) hr vs 1.69 (0.59-3.03) hr; P less than 0.01]. Cisapride also decreased mean small intestinal transit time of cellulose fiber [2.11 (0.80-5.08) hr vs 2.82 (0.78-7.12) hr; P less than 0.05] and plastic particles [2.06 (1.13-5.13) hr vs 2.64 (1.18-7.04) hr; P less than 0.05]. However, cisapride increased mean large intestinal transit time of plastic particles [31 (13-75) hr vs 23 (12-36) hr; P less than 0.05]. In conclusion, oral cisapride 10 mg four times a day accelerates gastric emptying and small intestinal transit whereas this dose of cisapride seems to delay large intestinal transit of solids in healthy humans.     

Effects of cisapride on distal esophageal motility in humans

Peristaltic contractions of the distal esophageal body and lower esophageal sphincter tone were evaluated in patients affected by gastroesophageal reflux disease after either acute intravenous (8.0 mg) administration or two oral doses (5.0 mg and 10.0 mg) of cisapride and in healthy controls after a 10.0-mg oral dose of cisapride. Intravenous cisapride administration enhanced the amplitude and duration of primary peristalsis and the lower esophageal sphincter tone, which reached normal control values. Likewise, the 10.0-mg oral dose effectively enhanced the lower esophageal sphincter resting pressure in both controls and in reflux patients, whereas the amplitude and duration of primary peristalsis was improved only in controls. The 5.0-mg oral dose of cisapride proved ineffective on distal esophageal motor activity in reflux patients. To evaluate whether atropine is capable of modifying the effects of cisapride on distal esophageal motor activity, cisapride was administered intravenously before and during intravenous atropine administration. Effects of cisapride on peristaltic contractions were completely blocked by atropine, irrespective of whether atropine was administered before or after cisapride. The lower esophageal sphincter pressure response to cisapride varied according to the sequence of drug administration, showing no effect when cisapride followed atropine administration and, when this sequence was reversed, no significant atropine-induced inhibition on cisapride-stimulated lower esophageal sphincter pressure. It is suggested that cisapride enhances distal esophageal motor activity by means of a muscarinic receptor mechanism at the level of the distal esophageal body and, at least in part, via a muscarinic-independent mechanism at the level of the lower esophageal sphincter.     

5-Hydroxytryptophan and carbidopa in spontaneously hypertensive rats

Serial measurements of blood pressure, body weight, food and water intake, and salt and water excretion were compared in two groups of spontaneously hypertensive rats (SHR) over a 12-day period: control SHR (n = 11) and a group (n = 9) which received supplementary 5-hydroxytryptophan (5-HTP; 2 mg/ml) in its drinking water. During the final 4 days of study, both groups received additional oral carbidopa (50 mg/kg twice a day) to inhibit peripheral, but not brain aromatic L-amino-acid decarboxylase (LAAD), an enzyme necessary to the formation of 5-hydroxytryptamine (5-HT, serotonin) from 5-HTP. 5-Hydroxytryptophan increased urinary 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) markedly; following carbidopa, urinary 5-HT, and to a lesser degree urinary 5-HIAA, decreased, whereas brain 5-HT and 5-HIAA increased. Spontaneously hypertensive rats treated with 5-HTP plus carbidopa had significantly lower blood pressure levels, lower pulse rates, reductions in food and water intake, salt and water excretion, and a loss of body weight, when compared with the control SHR. These data indicate that enhanced brain formation of 5-HT can give rise to metabolic and circulatory responses with a resultant lowering of blood pressure.     

针刺结合西沙必利对慢传输便秘大鼠结肠肌电的影响

目的:观察针刺、药物西沙必利及二者合用对慢传输便秘大鼠结肠肌电的影响, 探讨这3种治疗方法的效应差异, 以及针药结合的优势.方法:55只SD大鼠, 随机取10只作为正常组,其余45只用大黄小剂量递增灌胃造模. 测定大鼠结肠肌电慢波, 分别采用针刺足三里和照海、药物西沙必利及二者合用治疗14 d, 然后慢波的变化.结果:与正常大鼠比较, 部分模型大鼠慢波频率减慢为每分5.47±3.08次, 振幅降低为0.33±0.19 mV; 部分频率加快为每分26.61±8.99次, 振幅增高为0.69±0.70 mV. 对频率减慢、振幅降低型慢波的改变, 针刺组频率和振幅为每分8.36±5.55次, 0.42±0.21 mV; 药物组频率和振幅为每分6.84±3.44次, 0.20±0.03 mV;针药结合组频率和振幅为每分12.37±2.16次,0.37±0.05 mV. 对频率增快、振幅增高型慢波的改变, 针刺组频率和振幅为每分20.86±4.25次, 0.28±0.06 mV; 药物组频率和振幅为每分28.42±19.79次, 0.47±0.26 mV; 针药结合组频率和振幅为每分21.20±4.72次, 0.46±0.17 mV.结论:西沙必利只能单向地增快频率、升高振幅, 而针刺、针刺与西沙必利合用对模型大鼠频率与振幅的改变具有双向调整的作用.     

Postprandial antropyloroduodenal motility and gastric emptying in gastroparesis--effects of cisapride.

There is little information about the organisation of antroduodenal contractions or pyloric motility in patients with gastroparesis. The mechanisms responsible for the acceleration of gastric emptying by cisapride in patients with gastroparesis are also poorly understood. Simultaneous manometric and scintigraphic recordings were performed in 12 patients with gastroparesis and nine healthy volunteers before and after cisapride administration. Antropyloroduodenal pressures were recorded with a sleeve/side hole manometric assembly and gastric emptying with a scintigraphic method. Thirty minutes after the solid component of the test meal had begun to empty from the stomach all subjects received 5 mg cisapride intravenously over 10 minutes and recordings continued for a further 60 minutes. In the 30 minutes before cisapride there was no significant difference in the number of antral pressure waves (median 20 v 33, NS), basal pyloric pressure, or the number of isolated pyloric pressure waves between patients and volunteers, but the number of antral waves of extent > or = 6 cm (median 1 v 5, p < 0.05) was less in the patients, as was gastric emptying (8% v 20%, p < 0.05). In the patients, there was no change in the number of antral waves after cisapride, but there was an increase in the number of antral waves > or = 6 cm in extent (median 7 v 1, p < 0.05) and in the rate of gastric emptying (26% v 8%, p < 0.01). In the healthy subjects, cisapride increased gastric emptying (31% v 20%, p < 0.05), but reduced the number of antral waves (10 v 33, p < 0.05). Cisapride had no significant effect on the number of antral waves of extent more than or equal to 6 cm (11 v 5, NS). The number of isolated pyloric pressure waves decreased after cisapride (4 v 11, p < 0.05). There was a relationship between gastric emptying and the number of antral pressure waves of extent more than or equal to 6 cm in both the patients (r=0.38, p<0.05) and healthy subjects (r=0.05, p<0.01). There was no significant relationship between gastric emptying and the number of antral waves. It is concluded that disturbance of the relationship between antral, pyloric, and duodenal pressure waves is a major abnormality of postprandial gastric motor function in patients with gastroparesis. The stimulation of antral pressure waves of extent more than or equal to 6 cm may contribute to the acceleration of gastric emptying produced by cisapride in patients with gastroparesis and in normal subjects.     

Small intestinal motility and transit in disease

Disorders of small intestinal motility and transit are becoming increasingly recognized partly as a result of a greater awareness of their existence and partly because suitable diagnostic methods are more widely available. Usually, the neuropathic and myopathic forms can be separated, and gut disease secondary to a generalized neuromuscular disorder can be identified by the clinician. The availability of better non-invasive methods for the diagnosis of disorders of motility and transit would greatly facilitate their management. Treatment must include the restoration and maintenance of nutrition, attempts to improve intestinal motor function and resection of any segments of localized disease. Regrettably, all such measures are ineffective in the severest cases. In the future, a greater understanding of the enteric neural control of the smooth muscle and an ability to manipulate it with novel, specific drugs or peptidergic receptor agonists and antagonists, or electrical pacing, may lead to more effective therapies.     

Segmental gut transit in diabetes mellitus: effect of cisapride.

Gut transit using radiopaque markers was assessed in 5 healthy subjects and 24 diabetic patients. In the diabetics, various parameters including duration of the disease and diabetic complications, such as neuropathy, retinopathy and nephropathy, were determined, and the relationships between gut transit times and these complications were evaluated. The effect of cisapride on gut transit was studied in 10 diabetic patients. Large intestinal, descending colon, distal colon, and whole gut transit times were delayed in diabetics with autonomic neuropathy compared to controls and to diabetics without autonomic neuropathy (P less than 0.01). There was no difference in proximal colon transit times among them. An inverse correlation was observed between CVRR and the transit times for descending colon, distal colon, large intestine and whole gut. Large intestinal and whole-gut transit times were delayed in diabetics with retinopathy or with nephropathy compared to diabetics without those complications (P less than 0.01). In the diabetics, oral administration of 7.5 mg/day of cisapride for 2 weeks significantly accelerated descending colon transit (P less than 0.05) and partially accelerated distal colon, large intestinal and whole-gut transit. It is concluded that diabetics with autonomic neuropathy have delayed transits for the whole gut and that this finding is apparent to some extent in the distal colon but not in the proximal colon. Chronic oral administration of cisapride, a gastrointestinal prokinetic drug, was effective to improve these gastrointestinal motility disorders in diabetics with autonomic neuropathy.     

高频电针刺激足三里促进大鼠结肠推进运动

目的:通过高频电针刺激足三里穴观察大鼠结肠推进运动的改变,进一步验证电针刺激足三里穴对结肠运动的促进作用．方法:SD大鼠33只,随机分为3组,即针刺足三里组(组1)、电针非经穴组(组2)、电针足三里组(组3),每组11只．各组大鼠均以细软管将1个直径约3 mm的塑料小珠由肛门推入直肠3 cm处,分别记录正常情况下和给予相应刺激后的小珠排出时间．结果:组3刺激后小珠排出时间较刺激前增快约27％,有明显统计学差异(1142．8±123．9 vs 1563．5±155．9,P<0．01);而组1及组2刺激后小球排出时间与刺激前相比无统计学差异(P>0．05)．结论:高频电针刺激足三里穴对结肠推进运动有着显著的促进作用．     

Intrinsic propulsive activity of thoracic duct perfused in anesthetized dogs

We have investigated the regulation of the intrinsic smooth muscle propulsive activity of the thoracic duct in the anesthetized, ventilated dog. We cannulated both ends of the duct and, with the chest open and ventilation constant, perfused it with Krebs-Henselite buffer at constant inflow and outflow pressures. With inflow and outflow pressures equal (no net driving pressure) flow through the duct must be due to intrinsic smooth muscle contractions. When we increased transmural distending pressure of the thoracic duct, flow increased as distending pressure increased to 5 cm H₂O, then declined. Although there was no evidence of any basal neural stimulation of the duct, intravenous infusion of catecholamines increased flow. Their effects were blocked by phentolamine (α-blocker). 5-Hydroxytryptamine caused flow to increase, then decrease. The decrease appeared to be due to duct spasm, not inhibition. Constant intravenous infusions of histamine, prostaglandin E₁, and bradykinin either had no effect or inhibited flow. Intrinsic myogenic activity of the thoracic duct in the living animal may be a significant factor in lymph propulsion.     

Healing of grade-II and III oesophagitis through motility stimulation with cisapride

The clinical relevance of cispride's stimulating effects on lower oesophageal motility was studied in 19 patients with documented (endoscopy, biopsy) grade II or III oesophagitis. Patients were treated for 8 or 16 weeks (depending essentially on whether the result was cure or failure) with 10 mg of cisapride four times a day (n = 11) or placebo (n = 8). Cisapride was superior to placebo with regard to mucosal healing (p less than 0.001) and symptomatic improvement (p less than 0.05): at the end of treatment, healing (grade 0) was observed in 8 cisapride patients, against 1 placebo patient, and reflux symptoms had disappeared in 7 and 1 patients, respectively. In conclusion, cisapride was of significant benefit to oesophagitis patients and was well tolerated.