Ervin Y. Eaker

Effect of octreotide and erythromycin on idiopathic and scleroderma-associated intestinal pseudoobstruction

Treatment of chronic intestinal pseudoobstruction with prokinetic agents has been disappointing. Our study was designed to determine if octreotide and erythromycin would provide sustained relief from nausea, abdominal pain, and bloating in pseudoobstruction. Using gastrointestinal manometry, quantitative parameters of the activity front of the migrating motor complex at baseline and after prokinetic therapy with erythromycin and octreotide were determined in 14 patients with intestinal pseudoobstruction who had nausea, abdominal pain, and bloating. Patients were treated with erythromycin and octreotide for 20–33 weeks. Octreotide increased the frequency, duration, and motility index of activity fronts (AFs) from 1.2±0.3 AFs/4hr, 2.7±0.7 min, and 85±23 min mm Hg to 4.1±0.8 AFs/4 hr, 5.5±0.7 min, and 152±24 min mm Hg, respectively (P<0.05). Antral activity was decreased from 63±14 to 23±8% by octreotide (P<0.05). Erythromycin induced antral activity; however, small intestinal motor activity was suppressed. While on erythromycin and octreotide, five patients had long-term improvement of nausea and abdominal pain. All responders had at least 5 AFs/4 hr induced by octreotide. We conclude that octreotide and erythromycin relieve abdominal pain and nausea in pseudoobstruction. Patients who have at least 5 AFs/4 hr after octreotide administration are most likely to clinically respond.

Treatment of chronic constipation with colchicine: Randomized, double-blind, placebo-controlled, crossover trial

OBJECTIVE:Refractory constipation is a common GI complaint seen by physicians in all practice settings. We have previously shown that p.d. colchicine (0.6 mg t.i.d.) increases the number of spontaneous bowel movements, hastens GI transit, and improves GI symptoms in patients with chronic constipation during an 8-wk, open-label therapeutic trial. The aim of this study was to determine if p.d. colchicine will increase spontaneous bowel movements and accelerate colonic transit in patients with idiopathic chronic constipation in a randomized, placebo-controlled, crossover trial.METHODS:A total of 16 patients (15 women, one man) with a mean age of 47 yr (age range 25–89) with chronic idiopathic constipation who were refractory to standard medical therapy participated in the study. Patients randomly received either colchicine 0.6 mg p.o. t.i.d. or an identical placebo p.o. t.i.d. for a total of 4 wk in a double-blind, crossover fashion. Patients recorded their daily number of bowel movements and daily symptoms of daily nausea, abdominal pain, and bloating. Mean colonic transit was calculated at baseline, weeks 6 and 12.RESULTS:Colchicine increased the number of bowel movements and accelerated colonic transit compared with baseline and placebo conditions. There were no significant differences between conditions on ratings of nausea and bloating. During colchicine administration, mean abdominal pain was greater than the baseline or placebo conditions, however, the pain decreased significantly by the last week the patient was on colchicine.CONCLUSION:Colchicine increases the frequency of bowel movements and hastens colonic transit in patients with chronic constipation. Colchicine may be an effective agent available to practitioners to treat a subset of patients with chronic constipation who are refractory to standard medical therapy.

Colchicine Is an Effective Treatment for Patients with Chronic Constipation (An Open-Label Trial)

Chronic constipation is a common clinicalcondition that frequently does not respond to routinetherapeutic measures. We hypothesized that colchicinewould be effective in this condition because we reported that it stimulates intestinal motility in ratsand commonly causes diarrhea in patients taking the drugfor either gouty arthritis or Familial Mediterraneanfever. We prospectively studied seven patients with chronic constipation who were refractoryto medical therapy and treated them with oral colchicine0.6 mg per os three times a day for eight weeks in anopen-label pilot study. During the study, the mean number of spontaneous bowel movementssignificantly increased (P < 0.05) from 1.7 ±0.5 noted during routine therapy of constipation withlaxatives and enemas to 6.4 ± 0.7 per week; meancolonic transit time significantly (P < 0.05) decreased from58.1 ± 2.5 to 47.1 ± 5.0 hr; and symptomsof abdominal pain, nausea, and bloating significantly (P< 0.05) improved during therapy with colchicine. Oralcolchicine (0.6 mg three times a day) therapy appears tobe an a promising treatment for chronic constipation anda placebo-controlled trial is indicated to confirm thesefindings.

Erythromycin enhances gastric emptying in patients with gastroparesis after vagotomy and antrectomy

We studied the effect of erythromycin on gastric emptying in nine patients with gastroparesis following truncal vagotomy and antrectomy, and assessed their clinical response to chronic oral erythromycin. Gastric emptying was evaluated using a solid-phase radio-labeled meal. Patients were studied after erythromycin 200 mg intravenously (N=9) and after an oral suspension of erythromycin 200 mg (N=7) each given 15 min after ingestion of the meal. Three parameters of gastric emptying were analyzed: half-emptying time (T1/2), area under the curve, and percent gastric residual at 2 hr. Nine patients were subsequently placed on oral suspension erythromycin 150 mg three times a day before meals (range 125–250 mg three times a day) and symptoms of nausea, vomiting, postprandial fullness, and abdominal pain were assessed before and after erythromycin. Intravenous erythromycin markedly accelerated the gastric emptying (all three parameters studied) of solids (P<0.01) in seven of nine patients with postsurgical gastroparesis [baselineT1/2 154±15 min; after intravenous erythromycin,T1/2 56±17 min (mean ±sem)]. Oral erythromycin enhanced (P<0.05) the gastric emptying rate (T1/2, area under the curve) in five of seven patients (baselineT1/2 146±16 min; after oral erythromycin,T1/2 87±20 min). Of the nine patients who were placed on oral maintenance erythromycin, three showed clinical improvement after two weeks. In summary, erythromycin significantly enhances gastric emptying in many patients with vagotomy and antrectomy-induced gastroparesis; however, only a small subset of patients respond clinically to chronic oral erythromycin.

The distribution of novel intermediate filament proteins defines subpopulations of myenteric neurons in rat intestine

BACKGROUND/AIMS Recent studies with neurofilament antibodies as neuronal markers have shown subpopulations of myenteric neurons that do not contain neurofilament proteins. Novel neuronal intermediate filament proteins alpha-internexin, peripherin, and nestin have been identified. The aim of this study was to examine the distribution of these novel intermediate filaments in comparison with neurofilaments in myenteric plexus neurons. METHODS Using indirect immunofluorescence techniques in whole-mount cryostat sections from neonate and adult rat small intestine and in primary cultures of myenteric neurons, the distribution of neurofilaments, alpha-internexin, peripherin, and nestin was studied in comparison with the neuronal marker protein gene product (PGP) 9.5 in myenteric neurons. RESULTS Sixty-five percent of neurons contained neurofilament triplet proteins. alpha-Internexin and/or peripherin were found in the neurofilament-negative neurons. PGP 9.5 was present in 80% of the myenteric neurons. Of the neurons that were PGP negative, > 95% contained peripherin or alpha-internexin. Nestin was not found in either neonate or adult myenteric neurons but was seen in glial cells in culture. CONCLUSIONS The results suggest that a subpopulation of myenteric neurons lacks neurofilament triplet proteins but contains either peripherin, alpha-internexin, or both. This selective distribution of intermediate filaments in subpopulations of enteric neurons may support differential roles in these structurally unique neurons.

Case Report: Untoward Effects of Esophageal Botulinum Toxin Injection in the Treatment of Achalasia

Injection of botulinum toxin in the lower esophageal sphincter (LES) has recently been reported as a safer alternative in the treatment of achalasia (cardiospasm) (1, 2). Although symptomatic improvement is reported and some authors suggest botulinum injection as the preferred initial treatment (1), there are a number of bothersome issues that remain to be resolved. The length of symptomatic improvement appears to be shorter, and there appears to be a less impressive change in either LES pressure or esophageal emptying than that reported in most series after either pneumatic dilation or surgical myotomy (4 ± 6). Nonetheless, the side effects and complicat ions of esophageal botulinum toxin injection are reported to be minimal (1, 2), particularly in comparison to the inherent risks of surgery with myotomy or the approximately 4% perforation rate with dilation (3, 4). Chest pain at the time of injection is reported in 25% of patients, but is similar with either botulinum or saline injection (1). Development of gastroesophageal rē ux is rare but has been reported in two cases (7, 8), one with a peptic stricture (7); however, ulceration and hemorrhage have not been reported. We report a case of a patient with achalasia who developed several untoward and previously unreported side effects after esophageal botulinum toxin injection. These included gasroesophageal re ̄ ux with esophageal ulceration and hemorrhage and extraluminal esophageal in ̄ ammation discovered at myotomy. CASE REPORT

Neurofilament Immunoreactivity in Myenteric Neurons Differs From That Found in the Central Nervous System

Neurofilaments are 10-nm diameter protein fibers found within neurons and are composed predominantly of a triplet of polypeptides usually referred to as low-, medium-, and high-molecular-weight subunits. We describe the results of a study of myenteric plexus neurons using a panel of neurofilament triplet protein antibodies and indirect immunofluorescence techniques. Polyclonal antibodies to each of the three neurofilament subunits reliably stained myenteric neurons and their processes, indicating the presence of all three proteins in these cells. However, several well-characterized monoclonal antibodies to epitopes on high- and medium-molecular-weight subunits showed immunoreactivity in brain tissue but not in myenteric neurons and their processes. Some of the antibodies that do not stain recognize only phosphorylated epitopes, indicating that the level of neurofilament phosphorylation is very low in enteric neurons. Other antibodies that are not thought to be sensitive to the level of neurofilament phosphorylation show reduced or no staining of enteric neurons, suggesting the presence of immunologically distinct neurofilaments in these cells. These results suggest the presence of modified neurofilament structures in enteric neurons, possibly reflecting their unique mechanical character within the moving intestinal wall.

Endothelin-1 expression in myenteric neurons cultured from rat small intestine

Endothelin is a potent vasoactive peptide. More recently, endothelin-1 (ET-1) has been found in neural tissues such as spinal cord, brain and peripheral ganglion cells. Inagaki (Gastroenterology 101 (1991) 47) reported evidence of ET-1-like immunoreactivity in enteric neurons, but there are no reports of ET-1 peptide or mRNA expression specifically in myenteric neurons. Using a primary culture of myenteric neurons, we set out to evaluate ET-1 peptide and mRNA expression. Myenteric neurons were cultured using a dissection and enzyme dispersion technique. ET-1 reactivity was localized to neurons and ET-1 levels from cells and media were assayed by radioimmunoassay under a variety of media conditions or with depolarizing buffer or veratridine (75 microM). Prepro ET-1 mRNA expression was determined by Northern analysis of total RNA utilizing a rat ET-1 cDNA. ET-1 immunoreactivity was observed almost exclusively in myenteric neurons. Cells contained 0.78 pg/micrograms protein and did not vary with variations in media conditions. Basal release/secretion into media occurred but was not enhanced by depolarizing media or veratridine. High levels of ET-1 mRNA expression were identified. These results of high level constitutive expression of ET-1 linked with previous reports of ET-1 modulation of cholinergic intestinal smooth muscle contraction suggest a neuromodulatory role.

Presence of gonadotropin-releasing hormone (GnRH) receptor mRNA in rat myenteric plexus cells

Idiopathic neuromuscular disease of the gastrointestinal tract (functional bowel disease) is thought to result from the malfunction of neurons within the enteric nervous system. Gonadotropin-releasing hormone (GnRH) analogs have recently been shown to organize the disordered motility patterns typical in these patients and to produce significant, long-term symptomatic improvement. To determine whether GnRH analogs might bind to an endogenous enteric nervous system GnRH receptor, reverse transcription-polymerase chain reaction (RT-PCR) was performed using cultured neonatal rat enteric neuron RNA and rat GnRH receptor primers. A PCR product of the predicted size was cloned and nucleotide sequence analysis demonstrated that the myenteric plexus PCR product encoded a portion of the GnRH receptor sequence previously identified in rat pituitary. These results suggest that cells in the myenteric plexus express GnRH receptors that may bind exogenously administered GnRH analogs. The expression of GnRH receptors in enteric neurons would provide an explanation for the effectiveness of GnRH analogs in treatment of idiopathic neuromuscular disease of the gastrointestinal tract.

Effect of berberine on myoelectric activity and transit of the small intestine in rats

The motility of the small intestine in unanesthetized rats receiving berberine sulfate (0.2, 2.0, and 20.0 mg/kg i.p.) was investigated. Motility was determined by two methods: myoelectric activity was monitored with indwelling bipolar electrodes, and intestinal transit was measured by the movement of radiochromium (Na51CrO4). The 20.0-mg/kg dose caused a marked inhibition of spike activity for 21.8 +/- 7.0 min and disrupted activity fronts of the migrating myoelectric complex for 212.3 min. Berberine, 2.0 mg/kg i.p., disrupted migrating myoelectric complexes for 64.6 min but spike inhibition was not observed. Transit of the small intestine was significantly (p less than 0.001) delayed at 15 and 100 min after the highest dose of berberine. Naloxone blocked the spike inhibition noted with 20.0 mg/kg of berberine but failed to improve transit. Phentolamine blocked spike inhibition and was associated with a significantly earlier return of activity fronts of the migrating myoelectric complex. Animals pretreated with this antagonist tended toward a higher geometric center in transit studies than those injected with berberine alone. Berberine was also administered by various routes (intraperitoneal injection, intravenous injection, orogastric gavage, and intraluminal injection). An intraperitoneal injection was 10-fold more potent than an intravenous injection. Orogastric gavage and intraluminal administration of berberine did not alter intestinal motility. In summary, berberine sulfate significantly inhibits myoelectric activity and transit of the small intestine. This appears to be partially mediated by opioid and alpha-adrenergic receptors. The antidiarrheal properties of berberine may be mediated, at least in part, by its ability to delay small intestinal transit.