Food coloring and monosodium glutamate: effects on the cephalic phase of gastric acid secretion and gastrin release in humans.

Although food additives may have a significant impact on the marketing and acceptability of food and may occasionally lead to side effects, the effect of these additives on the digestive process in humans is unknown. We evaluated whether adding coloring or monosodium glutamate to food increases the cephalic phase of gastric acid secretion or gastrin release. When ordinary food coloring or unusual food coloring was added, acid secretion and gastrin release were similar to a control study with no food coloring added. Moreover, addition of 360 mg monosodium glutamate to beef consomme soup had no effect on the acid secretory or gastrin response to the meal. Thus, the food additives studied led to no objective alteration in the gastric exocrine or endocrine response to food.

Therapeutic uses of gastrointestinal peptides.

The GI tract is one of nature's great pharmacies. Most, if not all, biologically active peptides can be found there, and it is quite likely that others remain to be discovered. Our ability to exploit this resource has expanded considerably over the past two decades. Advances in analytical techniques have allowed investigators to rapidly isolate and purify new compounds from tissue extracts. Sequencing and de novo synthesis of newly discovered peptides are now routine, and the structural modifications required to alter activity and tailor a compound to a particular use are easily made. A number of gastrointestinal peptides or their analogues for use in clinical studies are available from commercial sources (see Table 7). Somatostatin is the first gut peptide to successfully complete development and yield a pharmaceutical compound with a broad range of action. Several of the peptides discussed in this article have similar potential. TRH stands out as a candidate because of its effectiveness in the treatment of experimental spinal cord injury and a variety of shock states. Such a broad range of action in critical fields may justify the intensive development required to yield potent, long-acting, and highly specific analogues. Similarly, the antimetastatic and immunostimulant properties of the enkephalins offer promise for new therapies in the treatment of AIDS, ARC, and cancer. Studies with amylin may lead to new and more precise regimens of blood sugar control in insulin-dependent diabetics and could in turn, prevent some of the worst long-term effects of the disease. The development of effective intranasal forms of GHRH could spare children with GH-GHRH deficiency the distress of repeated injections and help to prevent excessive GH blood levels. Secretin, glucagon, or CGRP might be used one day in cardiovascular emergencies, and VIP or its analogues could prove effective in the treatment of asthma. Although preliminary results with many of these peptides are encouraging, further progress will require the development of standardized experimental models and a more rigorous approach to experimental design. Many of the studies reported here suffered from small patient numbers, a narrow or nonexistent range of doses, or the use of only one or two dosing regimens. Lack of objective criteria for determining the level of response, e.g., in studies of mental illness or degenerative diseases, and the ethical problems of withholding treatment from some patients to establish proper controls further hamper research in this area. If the questions of efficacy and safety are to be resolved, thorough, well-planned trials will be required.

The action of loperamide in inhibiting prostaglandin-induced intestinal secretion in the rat.

1 The mechanisms by which loperamide inhibits the intestinal secretion induced by prostaglandin E2 were investigated in rat jejunum. 2 In vivo loperamide prevented prostaglandin-induced fluid secretion but did not reduce the associated rise in the transintestinal potential difference. 3 In intestinal sheets the electrical response to prostaglandin E2 was enhanced in the presence of loperamide. 4 The ionic basis of these changes was determined by measuring Na+ and Cl- fluxes across intestinal sheets. Loperamide did not reduce the prostaglandin-induced increase in net Cl- secretion, although it prevented the inhibition of mucosal-to-serosal Na+ movement. 5 Loperamide does not alter cyclic adenosine 3',5'-monophosphate (cyclic AMP) levels by a direct action at the enterocyte, since in isolated enterocytes neither basal nor prostaglandin-stimulated cyclic AMP levels were affected by the drug.

Octreotide treatment of carcinoid syndrome: analysis of published dose-titration data.

BACKGROUND: Octreotide has proven therapeutically effective in carcinoid syndrome, but the rarity of carcinoid tumors has hampered detailed dose-ranging studies. This study analysed published dose-titration data on octreotide use in carcinoid patients to (a) investigate the relation between octreotide dose and efficacy and (b) establish octreotide dosing recommendations for maximum therapeutic benefit. METHOD: An exhaustive, computer-assisted literature search for published articles employing octreotide to manage patients with carcinoid syndrome was performed using several databases. The relation between octreotide dose and efficacy in decreasing urinary 5-hydroxyindoleacetic acid (5-HIAA) levels, flushing and diarrhoea was analysed for seven dose ranges by pooling data from selected articles. RESULTS: Analysis of data compiled from 62 published studies revealed that maximum effective therapeutic doses of octreotide effectively controlled symptoms in up to 93% of patients, and that increasing the dose of octreotide is associated with increased benefit with respect to control of flushing, diarrhoea and 5-HIAA levels. CONCLUSIONS: We recommend starting octreotide therapy at 100 micrograms subcutaneously t.d.s. in patients with mild/moderate, non-life-threatening carcinoid syndrome. Since therapeutic response to octreotide varies markedly among patients, we recommend titrating the octreotide dose in increments of 50-100 micrograms every 8 h until adequate symptom control is achieved.

Inhibitory effect of isoprenaline on gastric acid secretion in the rat. The role of endogenous histamine.

In dogs beta-adrenoreceptor agonists inhibit gastric acid secretion stimulated by exogenous gastrin to a much greater extent than acid secretion stimulated by exogenous histamine. One possible explanation for this observation is that endogenous histamine is important in gastrin-mediated acid secretion and that isoprenaline and related beta-adrenoreceptor agonists block gastric mucosal histamine release. This possibility was tested in the present study in gastric lumen-perfused anaesthetized rats. Intravenous infusion of isoprenaline (12 microgram kg-1 h-1) inhibited maximal, pentagastrin-stimulated acid output by 50-70% (P less than 0.01), but had no significant inhibitory effect on the maximal acid secretory response to histamine. In contrast to its inhibitory effect on gastrin-stimulated acid output, isoproterenol had no effect on gastric histamine output during pentagastrin infusion. We conclude that isoprenaline selectively inhibits gastrin-stimulated acid secretion in the rat, as in the dog, and by a mechanism other than inhibiting gastric histamine release.

Effect of propranolol on secretin-induced gastrin release and secretin-induced tachycardia in patients with the Zollinger-Ellison syndrome.

The mechanism for secretin-induced gastrin release in the Zollinger-Ellison syndrome is uncertain. We evaluated whether the stimulatory effect of intravenous secretin on gastrin release was partly mediated through a beta-adrenergic stimulatory mechanism. Serum gastrin concentrations and heart rate were monitored in six patients with the Zollinger-Ellison syndrome. Secretin (2 clinical units/kg) increased mean serum gastrin concentrations from 1558 pg/ml basally to a peak of 3683 pg/ml (136% above baseline). This increase was not altered by pretreatment with 2 mg of propranolol intravenously, a dose which in previous studies blocked terbutaline-induced gastrin release. Secretin increased heart rate by 14 beats/min (20% above base-line) and this also was not altered by propranolol pretreatment. Thus, the stimulatory effects of secretin on gastrinoma cells and the heart do not appear to be mediated by beta-adrenergic receptors.

Lack of pharmacokinetic interaction between rofecoxib and methotrexate in rheumatoid arthritis patients.

Rofecoxib is a highly selective and potent inhibitor of cyclooxgenase-2 (COX-2). Methotrexate is a disease-modifying agent with a narrow therapeutic index frequently prescribed for the management of rheumatoid arthritis. The objective of this study was to investigate the influence of clinical doses of rofecoxib on the pharmacokinetics of methotrexate in patients with rheumatoid arthritis. This was a randomized, double-blind, placebo-controlled study in 25 rheumatoid arthritis patients on stable doses of methotrexate. Patients received oral methotrexate (7.5 to 20 mg) on days -1, 7, 14, and 21. Nineteen patients received rofecoxib 12.5, 25, and 50 mg once daily on days 1 to 7, 8 to 14, and 15 to 21, respectively. Six patients received placebo on days 1 to 21 only to maintain a double-blinded design for assessment of adverse experiences. Plasma and urine samples were analyzed for methotrexate and its major although inactive metabolite, 7-hydroxymethotrexate. The AUC(0-infinity) geometric mean ratios (GMR) and their 90% confidence intervals (90% CI) (rofecoxib + methotrexate/methotrexate alone) for day 7/day -1, day 14/day -1, and day 21/day -1, for rofecoxib 12.5, 25, and 50 mg, were 1.03 (0.93, 1.14), 1.02 (0.92, 1.12), and 1.06 (0.96, 1.17), respectively (p > 0.2 for all comparisons to day -1). All AUC(0-infinity), GMR and Cmax GMR 90% CIs fell within the predefined comparability limits of (0.80, 1.25). Similar results were observed for renal clearance of methotrexate and 7-hydroxymethotrexate at the highest dose of rofecoxib tested (50 mg). It was concluded that rofecoxib at doses of 12.5, 25, and 50 mg once daily has no effect on the plasma concentrations or renal clearance (tested at the highest dose of rofecoxib) of methotrexate in rheumatoid arthritis patients.

[Serum uric acid--a cardiovasular risk factor?]. / Harnsäure, ein kardiovaskulärer Risikofaktor?

Serum uric acid represents an important, independent risk factor for cardiovascular and renal disease in patients with hypertension, heart failure, or diabetes. Elevated serum uric acid is highly predictive of mortality in patients with heart failure or coronary artery disease and of cardiovascular events in patients with diabetes. Although the mechanism(s) by which uric acid may play a pathogenetic role in cardiovascular disease is unclear, hyperuricemia is associated with deleterious effects on endothelial dysfunction, oxidative metabolism, platelet adhesiveness, hemrheology, and aggregation. Whether a reduction in uric acid impacts CV and renal disease remains to be determined. However, recent findings from LIFE in hypertensive patients with LVH suggest the possibility that a treatment-induced decrease in serum uric acid may indeed attenuate cardiovascular risk. Almost one third of the treatment benefit of a losartan-based versus atenolol-based therapy on the composite endpoint (death, myocardial infarction, or stroke) may be ascribed to differences in achieved serum uric acid levels. Clearly, randomized clinical trials are needed to investigate further the long-term cardioprotective benefits issue of reducing hyperuricemia in hypertensive patients.

Prostaglandin synthesis and catabolism in the gastric mucosa: studies in normal rabbits and rabbits immunized with prostaglandin E2.

Antral and fundic mucosal homogenates obtained from prostaglandin E2-immunized rabbits converted 14C-arachidonic acid to prostaglandin E2, 6-keto prostaglandin F1 alpha, prostaglandin F2 alpha, and prostaglandin D2. Percentage conversion of 14C-arachidonic acid to these prostaglandin products was not significantly different in prostaglandin E2-immunized rabbits compared with control rabbits (thyroglobulin-immunized and unimmunized rabbits combined). Synthesis of 6-keto prostaglandin F1 alpha, prostaglandin E2 and 13,14-dihydro 15-keto prostaglandin E2 from endogenous arachidonic acid after vortex mixing fundic mucosal homogenates was similar in prostaglandin E2 immunized rabbits and control rabbits. Both in prostaglandin E2-immunized rabbits and controls, 3H-prostaglandin E2 was catabolized extensively by the fundic mucosa, whereas 3H-6-keto prostaglandin F1 alpha, 3H-prostaglandin F2 alpha, and 3H-prostaglandin D2 were not catabolized to any appreciable extent. The rate of catabolism of PGs was not significantly different in prostaglandin E2-immunized rabbits and control rabbits, with the exception of prostaglandin F2 alpha which was catabolized slightly more rapidly in prostaglandin E2-immunized rabbits. These results indicate that development of gastric ulcers in prostaglandin E2-immunized rabbits is not associated with an alteration in the capacity of the gastric mucosa to synthesize or catabolize prostaglandins.

Octreotide-associated biliary tract dysfunction and gallstone formation: pathophysiology and management.

Octreotide exerts a wide range of biological actions, many of which have important clinical applications, notably in treatment of acromegaly, gastroenteropancreatic endocrine tumors, and secretory diarrhea. In most patients, octreotide is well tolerated. Side effects are primarily gastrointestinal and are usually transient. Short term (< or = 1 month) octreotide therapy appears to pose minimal risk of gallstone formation, but the risk may increase with longer treatment periods. Chronic octreotide administration may increase the incidence of small, cholesterol gallstones that are typically asymptomatic. The mechanism of octreotide-associated gallstone formation is not delineated but may involve inhibition of gallbladder emptying, hepatic bile secretion, and sphincter of Oddi motility, as well as modification of bile composition. Gallbladder stasis may sequentially lead to increased bile concentration, precipitation of cholesterol and calcium salts, retention of biliary precipitates, and maturation of gallstones. Octreotide-associated gallstones are usually asymptomatic and do not require surgical or medical therapy. Some physicians advocate periodic gallbladder ultrasound evaluations, but, in most cases, the results would not influence management of asymptomatic patients. Symptomatic gallstones may require surgery or nonsurgical treatments after an appropriate work-up. Gallstone prevention strategies (e.g., bile acid or nonsteroidal anti-inflammatory drug therapy) during long term octreotide therapy are under investigation. Currently, clinicians may want to consider noninvasive strategies to reduce gallstone incidence, such as timing octreotide injections in relation to meals or periodic cessation of octreotide treatment. Octreotide is a valuable therapeutic option in managing a variety of hypersecretory states associated with high morbidity and mortality (e.g., acromegaly, carcinoid syndrome, and VIP-secreting tumors), so the benefits of long term octreotide therapy (such as increased quality of life) outweigh the risk of asymptomatic gallstone formation in many patients.

Lack of specific binding of prostaglandin E2, prostaglandin F2 alpha, and 6-keto prostaglandin F1 alpha to serum in patients with peptic ulcer disease and in healthy subjects.

Rabbits immunized against prostaglandins develop antibodies to prostaglandins and peptic ulcer disease (duodenal and gastric ulcers). We have evaluated the hypothesis that idiopathic gastric or duodenal ulcer disease in humans may be associated with the spontaneous occurrence of serum antibodies directed against endogenous prostaglandins. We found that serum from 45 ulcer patients (34 duodenal, 11 gastric) had a low degree of binding of radiolabeled prostaglandin E2, prostaglandin F2 alpha, or 6-keto prostaglandin F1 alpha. The extent to which prostaglandins were bound to serum of ulcer patients was not statistically different from prostaglandin binding to serum from 25 normal subjects. Therefore, we conclude that spontaneous occurrence of circulating antibodies against endogenous prostaglandins is an unlikely cause of gastroduodenal ulceration in humans.

Role of endogenous prostaglandins in preventing gastrointestinal ulceration: induction of ulcers by antibodies to prostaglandins.

Active immunization of rabbits with the principal, endogenous prostaglandins in the gastrointestinal mucosa induces gastrointestinal mucosal ulceration. Development of ulceration in prostaglandin-immunized rabbits appears to be a direct consequence of production of specific prostaglandin antibodies, as prostaglandin antibodies per se induce gastric ulceration within 9 days when administered intravenously to unimmunized rabbits. These studies suggest that endogenous prostaglandin E2, F2 alpha, D2, and I2 in the gastrointestinal tract play an important role in preventing mucosal ulceration. The mechanism of ulcer formation is not completely understood, but most evidence points toward prostaglandin antibodies inducing mucosal ulceration by binding to endogenous prostaglandins within the mucosa and thereby negating their mucosal protective effects. Gastric acid hypersecretion and complement fixation by prostaglandin-antiprostaglandin complexes are not likely involved in the development of mucosal ulceration in this model. Use of antibodies to interfere with prostaglandin action may be an alternative approach to investigate (a) the importance of endogenous prostaglandins in mediating mucosal protective mechanisms and (b) the role of prostaglandins in acute and chronic erosive/ulcerative diseases of the gastrointestinal tract.

Action of 5-hydroxytryptamine on intestinal ion transport in the rat.

1. 5-HT increased the electrical activity of rat jejunum both in vivo and in vitro. The increased potential difference and short-circuit current resulted from a stimulation of electrogenic chloride secretion. NaCl absorption may also have been inhibited. 2. 5-HT did not alter cyclic AMP levels in isolated enterocytes. 3. The 5-HT response in vivo was unaffected by atropine, cyproheptadine, propranolol and hexamethonium. Phenoxybenzamine reduced the maximum response without affecting the dose required to produce a 50% maximum response. Methysergide, at a dose of 40 mg/kg, had a similar effect while a lower dose of 2 mg/kg produced no change. Mianserin competitively antagonized the response to 5-HT, a dose of 2 mg/kg producing a fourfold increase in the amount of 5-HT required to produce a 50% maximum response. 4. Acetylcholine and 5-HT seem to act independently in inducing intestinal secretion since atropine did not block the response to 5-HT and Mianserin did not alter the response to acetylcholine. 5. Experiments in which the intestinal villi or crypts were subjected to preferential damage suggested that 5-HT primarily produced its response at the crypt cell level.

Effect of indomethacin on gastric mucosal prostaglandins in humans. Correlation with mucosal damage.

We evaluated in healthy human beings the effect of indomethacin on gastric mucosal prostaglandin concentration and on gastric mucosal damage in a placebo-controlled study. Prostaglandin E2, prostaglandin F2 alpha, and 6-keto prostaglandin F1 alpha concentrations of gastric mucosal biopsy specimens, obtained endoscopically, were measured by radioimmunoassay. Mean prostaglandin concentration of the antrum and fundus was similar. In both regions there was considerable intersubject variability in prostaglandin concentration. Repeated 50-mg oral doses of indomethacin for 4 days reduced mean prostaglandin F2 alpha and E2 concentration by 50.2% and 69.4%, respectively, in the fundus and by 40.0% and 49.7% in the antrum, but this led to no significant mucosal damage when assessed endoscopically or histologically. A single 100-mg oral dose of indomethacin reduced mean prostaglandin F2 alpha and prostaglandin E2 concentration by 81.4% and 60.9% in the fundus and by 64.2% and 57.5% in the antrum and also induced significant mucosal injury in both regions when assessed endoscopically. However, there was no correlation between degree of suppression of prostaglandin concentration by indomethacin and endoscopic evidence of mucosal damage.

Effect of immunization with prostaglandin metabolites on gastrointestinal ulceration.

Active immunization of rabbits with a 6-ketoprostaglandin F1 alpha-thyroglobulin conjugate induced gastrointestinal ulceration, whereas active immunization of rabbits with 13,14-dihydro-15-keto prostaglandin E2-thyroglobulin conjugate or with thyroglobulin alone did not result in ulceration. Passive immunization of a separate group of rabbits with 6-ketoprostaglandin F1 alpha-hyperimmune plasma, obtained from actively 6-ketoprostaglandin F1 alpha-immunized donor rabbits that had ulcers, induced gastric ulceration within 9 days, whereas passive immunization of rabbits with control plasma, obtained from donor rabbits actively immunized with thyroglobulin alone, did not induce ulceration. Ulcerogenic donor plasma containing antibody to 6-ketoprostaglandin F1 alpha neutralized the inhibitory actions of prostacyclin on adenosine diphosphate-induced platelet aggregation, indicating that this antibody cross-reacted with prostacyclin. In contrast, plasma containing antibodies to 13,14-dihydro-15-ketoprostaglandin E2 cross-reacted only slightly with prostaglandin E2. Thus antibodies to inactive metabolites of prostaglandins induce ulceration only if these antibodies cross-react with an endogenous, "cytoprotective" prostaglandin.

Comparison of salsalate and aspirin on mucosal injury and gastroduodenal mucosal prostaglandins.

The effects of a 7.5-day course of orally administered salsalate (3.0 g/day), aspirin (3.9 g/day), or placebo on gastroduodenal mucosal injury, mucosal prostaglandin content, and plasma prostaglandin concentrations in healthy, asymptomatic human volunteers were examined. Mean serum salicylate concentrations after these doses of salsalate and aspirin were nearly identical (approximately 15 mg/dL). When the gastroduodenal mucosa was assessed endoscopically 1 hour after the final dose of medication, there was minimal mucosal injury in placebo-treated or salsalate-treated subjects and considerable injury in the stomach and duodenum of aspirin-treated subjects (P less than 0.001, aspirin vs. salsalate or placebo). In both the stomach and duodenum, aspirin lowered mucosal prostaglandin F2a and E2 content by greater than 90% (P less than 0.001), whereas salsalate produced no significant change. Aspirin also lowered plasma prostaglandin F2a concentrations by 58% +/- 6%, whereas salsalate lowered them by only 11% +/- 9% (P less than 0.001). Thus, the nonacetylated salicylate, salsalate, produced much less gastroduodenal mucosal damage than aspirin at equivalent serum salicylate concentrations, possibly because salsalate did not inhibit mucosal prostaglandin synthesis.

Effects of fish oil on gastric mucosal 6-keto-PGF1 alpha synthesis and ethanol-induced injury.

Fundic mucosal content and synthesis of 6-ketoprostaglandin F1 alpha, the major prostanoid in the rat gastric mucosa, were determined after rats had ingested a diet containing 10% fish oil or 10% corn oil for 4 wk. 6-Ketoprostaglandin F1 alpha content and synthesis in rats fed a fish oil-supplemented diet were reduced significantly compared with rats receiving a corn oil-supplemented diet (P less than 0.05). However, rats receiving 10% fish oil for 8 wk sustained significantly less gastric mucosal injury after intragastric challenge with 15% and then with absolute ethanol than rats receiving 10% corn oil or regular chow for 8 wk (P less than 0.05). Thus fish oil ingestion protected the gastric mucosa even though fish oils reduced mucosal prostaglandin synthesis.

Localization of the effect of acetylcholine in regulating intestinal ion transport.

1. The location of the site involved in the secretory response of rat jejunum and colon to ACh was investigated by selectively damaging either the villi of the jejunum and the surface epithelium of the colon or the crypts. 2. The secretory response induced by ACh was measured both in terms of changes in electrical activity and chloride fluxes. 3. Exposure of the mucosa to 2 M-Na2SO4 for 30 min selectively damaged the jejunal villi and colonic surface epithelium but did not reduce the increased potential difference and current generated by ACh. 4. When resistance changes were taken into account the colonic response was markedly increased after Na2SO4 treatment although the jejunal response was unchanged. Under control conditions ACh reduced net Na absorption and stimulated Cl secretion by the colon. After exposure to Na2SO4 only the Cl secretory component of the ACh response remained, thus accounting for the enhanced effect. 5. Cycloheximide, administered I.V. at a dose of 12 mg/kg, damaged the crypts after 2 hr without affecting the villi of the jejunum or the surface epithelium of the colon. After cycloheximide treatment the increased potential difference, current and net Cl secretion induced by ACh were significantly reduced. 6. The crypts therefore appear to be the site primarily involved in the secretory response of rat jejunum and colon to ACh, although in the colon an inhibitory effect on the Na transport process located in the surface epithelium was observed.