Survey of laxative use by adults with self-defined constipation in South America and Asia: a comparison of six countries.

BACKGROUND: In contrast to the US and Europe, prevalence and laxative use for self-defined constipation among adults was previously reported to be unassociated with age among adults in South Korea and Brazil. AIM: To determine whether observations in South Korea and Brazil are reflective of other Asian and South American countries. METHODS: A total of 8100 adults from Argentina, Colombia, Indonesia and China completed a questionnaire identical to that previously used in South Korea and Brazil. RESULTS: Prevalence of constipation was similar to that reported for Brazil and South Korea and was 2.17-fold (95% CI: 1.71-2.64) higher amongst women than amongst men. Prevalence increased with age amongst all adults in Argentina and China and only among men in Colombia and Brazil. With the exception of Indonesia, the majority of those with constipation had symptoms at least once weekly, and for < or =3 years. Less than one-third of adults reported using laxatives to treat constipation. Laxative use was not associated with gender and increased with age in Argentina and Colombia. CONCLUSIONS: No clear geographical or cultural tendencies were observed in the prevalence of constipation and laxative use among the South American and Asian countries studied in this survey.

A multinational survey of prevalence and patterns of laxative use among adults with self-defined constipation.

BACKGROUND: While numerous studies report prevalence of constipation, use of laxatives is poorly understood. AIM: To conduct a survey in seven countries evaluating prevalence of constipation and laxative use in its treatment. METHODS: Thirteen thousand eight hundred seventy-nine adults [approximately 2000 each from US, UK, Germany (GE), France (FR), Italy (IT), Brazil (BR) and South Korea (SK)] completed questionnaires assessing occurrence, frequency, duration and laxative use for treating constipation. RESULTS: Overall, 12.3% of adults had constipation [range: 5% (GE) to 18% (US)] in the prior year. A greater percent of women from all countries and elderly from all except SK and BR reported constipation; odds ratios for constipation among women and elderly were 2.43 (95% CI: 2.18-2.71) and 1.5 (95% CI: 1.25-1.73) vs. men and young subjects. Among those with constipation, 16% (SK) to 40% (US) used laxatives. Laxative use was generally associated with increasing age, symptom frequency and lower income and education. A similar percentage of men and women with constipation reported using laxatives; a greater percentage of women used laxatives for a longer time. CONCLUSIONS: Prevalence of self-defined constipation and laxative use varies among countries. Prevalence is generally related to gender and age, whereas laxative use is related to age, but not to gender.

Review article: alginate-raft formulations in the treatment of heartburn and acid reflux.

Alginate-based raft-forming formulations have been marketed word-wide for over 30 years under various brand names, including Gaviscon. They are used for the symptomatic treatment of heartburn and oesophagitis, and appear to act by a unique mechanism which differs from that of traditional antacids. In the presence of gastric acid, alginates precipitate, forming a gel. Alginate-based raft-forming formulations usually contain sodium or potassium bicarbonate; in the presence of gastric acid, the bicarbonate is converted to carbon dioxide which becomes entrapped within the gel precipitate, converting it into a foam which floats on the surface of the gastric contents, much like a raft on water. Both in vitro and in vivo studies have demonstrated that alginate-based rafts can entrap carbon dioxide, as well as antacid components contained in some formulations, thus providing a relatively pH-neutral barrier. Several studies have demonstrated that the alginate raft can preferentially move into the oesophagus in place, or ahead, of acidic gastric contents during episodes of gastro-oesophageal reflux; some studies further suggest that the raft can act as a physical barrier to reduce reflux episodes. Although some alginate-based formulations also contain antacid components which can provide significant acid neutralization capacity, the efficacy of these formulations to reduce heartburn symptoms does not appear to be totally dependent on the neutralization of bulk gastric contents. The strength of the alginate raft is dependant on several factors, including the amount of carbon dioxide generated and entrapped in the raft, the molecular properties of the alginate, and the presence of aluminium or calcium in the antacid components of the formulation. Raft formation occurs rapidly, often within a few seconds of dosing; hence alginate-containing antacids are comparable to traditional antacids for speed of onset of relief. Since the raft can be retained in the stomach for several hours, alginate-based raft-forming formulations can additionally provide longer-lasting relief than that of traditional antacids. Indeed, clinical studies have shown Gaviscon is superior to placebo, and equal to or significantly better than traditional antacids for relieving heartburn symptoms. Alginate-based, raft-forming formulations have been used to treat reflux symptoms in infants and children, and in the management of heartburn and reflux during pregnancy. While Gaviscon is effective when used alone, it is compatible with, and does not interfere with the activity of antisecretory agents such as cimetidine. Even with the introduction of new antisecretory and promotility agents, alginate-rafting formulations will continue to have a role in the treatment of heartburn and reflux symptoms. Their unique non-systemic mechanism of action provides rapid and long-duration relief of heartburn and acid reflux symptoms.

Fatty acid-mediated gastroprotection does not correlate with prostaglandin elevation in rats exposed to various chemical insults.

This study involved a comparison of activity of several long-chain fatty acids (arachidonic acid, dihomo-[gamma]-linolenic acid, linoleic acid, and oleic acid) for protection against gastric mucosal damage elicited by taurocholic acid, acidified aspirin, and ethanol in rats. Each damaging agent induced gastric mucosal lesions in the corpus. Mucosal damage was induced by all agents, and all fatty acids protected the gastric mucosa; however, ethanol and arachidonic acid were the most potent damaging and protecting agents, respectively. Maximally protective doses for prevention of taurocholic acid-induced damage by arachidonic, dihomo-[gamma]-linolenic, linoleic, and oleic acids were 50, 200, 100, and 200 mg/kg, respectively; however, 10 mg/kg arachidonic acid reduced lesion length by > 50%, whereas minimally effective doses of the other fatty acids were > or = 50 mg/kg. Similar potency differences were observed for fatty acid protection against acidified aspirin-induced gastric damage. Although all the fatty acids reduced macroscopic damage, histologic studies showed they did not totally eliminate surface mucosal damage. Microscopic analysis showed that treatment with dihomo-[gamma]-linolenic acid or oleic acid attenuated depletion of neutral and acidic glycoproteins from the mucus neck cells of the gastric mucosa in response to exposure to taurocholic acid. Despite having similar gastroprotective activity, arachidonic, dihomo-[gamma]-linolenic, linoleic, and oleic acids had very dissimilar abilities to elevate gastric mucosal E-series prostaglandins. Both arachidonic and dihomo-[gamma]-linolenic acids elevated E-series prostaglandins, but arachidonic acid had 2-5-fold greater gastroprotective potency. Furthermore, oleic and linoleic acids, which had protective potency similar to that dihomo-[gamma]-linolenic acid, did not significantly elevate prostaglandins. These studies failed to demonstrate an absolute correlation between prostaglandin elevation and gastroprotection. The results of this investigation suggest that prostaglandin elevation, although associated with gastroprotection, does not appear to be the sole mechanism for fatty acid-mediated protection of rat gastric mucosa.

Neurokinin3 receptor regulation of acetylcholine release from myenteric plexus.

This study sought to characterize the action of neurokinin B (NKB) and senktide, a selective synthetic agonist for NK3 receptors, on the myenteric plexus of the guinea pig small intestine. Both peptides stimulated a dose-dependent release of [3H]-acetylcholine (ACh). The mean effective dose values were 1 x 10(-9) for NKB and 3 x 10(-11) M for senktide. The action of these two neurokinins was blocked by the removal of Ca2+ and was sensitive to tetrodotoxin. The release of [3H]ACh was antagonized by omega-conotoxin GVIA, implying the involvement of N-type voltage-sensitive calcium channels. Senktide-evoked ACh release was also insensitive to nifedipine or flunarizine but was blocked by diltiazem. Treatment with protein kinase C (PKC) inhibitors (H-7 and polymyxin B) or activators (12-tetradecanoylphorbol 13-acetate and SC-9) failed to alter the NK3 receptor-mediated ACh output. Our data did not support an action mediated via PKC upon the activation of NK3 receptors on myenteric cholinergic neurons.

Effect of mebeverine hydrochloride on jejunal motility and epithelial transport in the anesthetized ferret.

Previous in vitro and in vivo studies demonstrate that mebeverine, administered to isolated smooth muscle preparations or given intravenously, (i.v.), acts as an antispasmodic agent and may be useful in treating intestinal hypermotility. Whether mebeverine affects intestinal mucosal transport is, however, unknown. The aim of the present study was to characterize the effect of mebeverine on both small intestinal motor activity and electrogenic epithelial transport in the urethane anesthetized ferret. The effects of mebeverine were compared following i.v. and intrajejunal (i.j.) administration. Following both routes of drug administration mebeverine dose dependently inhibited jejunal motility, with the i.j. route being more potent. However, when administered i.v. but not i.j., the doses of mebeverine that inhibited jejunal motility also significantly reduced heart rate and arterial blood pressure. Mebeverine (0.1-10 mg/kg) administered i.v. had no significant effect on epithelial transport as measured by a change in transmural potential difference. However, when dosed i.j., mebeverine (0.1-10 mg/kg) induced a decrease in potential difference towards lower lumen negativity, which was suggestive of a decrease in fluid secretion or enhancement of absorption. In conclusion, the results confirm in vivo the antispasmodic effect of mebeverine and suggested that mebeverine can influence epithelial transport, probably in the direction of enhanced intestinal absorption.

Irradiation of pigmented melanoma cells with high intensity pulsed radiation generates acoustic waves and kills cells.

Photokilling of pigmented mouse melanoma cells (B-16) was investigated using pulsed high intensity visible radiation. Melanin acts as an endogenous chromophore, and 694 nm radiation with 40 nsec pulse duration and 0.5-3 X 10(7)w/cm2 intensity causes cell death. Irradiation of non-pigmented human melanoma cells (U1) or human squamous carcinoma cells (FaDu) under similar conditions did not kill the cells. Also, irradiation of B-16 cells with 300 microsec laser pulses (10(3)W/cm2) or with continuous wave (CW) radiation (10(-3)W/cm2) did not kill the cells. These data indicate that pigmented cell killing is due to absorption of radiation by melanin and that the pulsewidth and intensity of radiation play important roles in cell killing. The generation of acoustic waves due to absorption of the pulsed radiation by pigmented cells and by isolated melanosomes was demonstrated at 532 and 625 nm and 8.5 nsec pulse duration (10(7)-10(8) W/cm2); the amplitudes of the acoustic signals were approximately 2.5-3.0-fold higher at 532 nm compared with 625 nm, and they increased with increasing fluence. In contrast, irradiation of U1 or FaDu cells with comparable fluences and intensities did not generate acoustic waves. A possible correlation between the generation of photoacoustic waves and pigment cell death is proposed. Since the thermal relaxation time of melanosomes is 0.5-1.0 microsec, the mechanism proposed is that thermal confinement of high intensity, short-pulse visible radiation generates acoustic waves by thermal expansion, leading to mechanical damage to the cells.

In vivo assessment of precursor induced prostaglandin release within the rat gastric lumen.

Gastroprotection associated with the intragastric administration of prostaglandin (PG) precursor fatty acids such as linoleic (LA), gamma-linolenic (GLA), and arachidonic acid (AA) has been reported to be mediated via their conversion to PGs. This report examines the relationship between gastroprotection and the extent/rate of PG-release in rats intragastrically administered PG biosynthetic precursors: LA, AA, dihomo-gamma-linolenic acid (DHGL) or oleic acid (OA, a nonprecursor fatty acid). At various times following intragastric administration of a fatty acid, gastric fluid was collected, extracted, chromatographed, and assayed for PGE1 or PGE2 by specific radioimmunoassay. AA and DHGL dose dependently elevated gastric PGE2 and PGE1 levels, respectively. Maximal PGE elevation, 200-400 ng/stomach, was over 400-fold above basal values, and observed within 5-10 minutes of administration. Conversely, OA and LA elicited only a minor (2-10 fold) stimulation of PGE release. In contrast to effects on PG release, all four fatty acids protected the gastric mucosa against macroscopic damage induced by ethanol. The apparent rank order of potency was AA greater than DHGL = LA greater than OA (the difference in potency between DHGL or LA and OA was not significant). Since LA and OA (a nonprecursor) only marginally elevated lumenal PGs relative to DHGL or AA, yet were equally efficacious in the gastroprotection assay, it is likely that other fatty acid-related mechanisms play an important role in protecting the stomach against ethanol-induced injury.

Inhibition of ATP levels by quinidine in a human colonic epithelial cell line.

The influence of quinidine, a putative K+ channel blocker, on Cl- secretion induced by vasoactive intestinal polypeptide (VIP) was investigated. Quinidine inhibited Cl- secretion induced by VIP in T84 cell monolayers. A similar inhibitory effect of quinidine on Cl- secretion was observed in an isolated human colon. However, in the isolated human colon, which absorbs Na+ avidly, inhibition of Na+ absorption predominated. In the T84 cell, the half-maximal inhibition by quinidine occurred at 60 microM, while 300 microM almost completely inhibited the VIP-induced Cl- secretion. Mucosal addition of quinidine was at least equally effective compared with serosal addition, suggesting that quinidine acts on the apical membrane or intracellularly. Quinidine had little or no effect on VIP-stimulated Cl- efflux in the first 15 min after its addition, suggesting that blockage of the Cl- exit pathway on the apical membrane is an unlikely mechanism. Similarly, quinidine did not inhibit the K+-recycling mechanism on the basolateral membrane in the first 15 min after its addition. The initial inhibitory action of quinidine corresponded better with its ability to decrease cellular ATP levels. Our study suggests that the depletion of cellular ATP levels may explain the initial inhibitory action of quinidine on electrolyte transport in the intestine, while the late effect is multifactorial.

Ba2+ inhibition of VIP- and A23187-stimulated Cl- secretion by T84 cell monolayers.

Addition of either 10(-8) M vasoactive intestinal polypeptide (VIP) or 10(-6) M A23187 to T84 cell monolayers, grown on permeable supports and mounted in Ussing chambers, stimulated net Cl- secretion. The effect of 10(-6) M A23187 on Cl- flux was consistently smaller than that observed with 10(-8) M VIP. In both cases the increase in net Cl- secretion accounted for the entire change in the observed short-circuit current (Isc). Since Cl- enters the cells through a basolaterally localized Na+-K+-Cl(-)-cotransport system (J. Clin. Invest. 75: 462, 1985), the fate of K+, which is cotransported with Cl- during VIP, and A23187-mediated Cl- secretion was explored. Unidirectional and net transepithelial 42K+ flux rates were negligible compared with 36Cl- flux rates (less than 4% of Cl- flux), indicating that little K+ was secreted along with Cl-. K+ recycling across the basolateral membrane was suggested from experiments in which 86Rb+ efflux (as a tracer for K+) was measured across the apical and basolateral membranes of 86Rb+ -preloaded monolayers under voltage-clamped conditions. In the absence of secretagogues, 86Rb+ efflux was 10-fold higher across the basolateral membrane than across the apical membrane. 86Rb+ efflux across the basolateral membrane was accelerated two- to threefold by addition of either VIP or A23187. In each case accelerated efflux was inhibited by 5 mM Ba2+. Cl- secretion induced by VIP or A23187 was also inhibited by serosal addition of Ba2+.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of a cyclic AMP-activated Cl-transport pathway in the apical membrane of a human colonic epithelial cell line.

This report describes a Cl- transport pathway in confluent monolayer cultures of the T84 human colonic carcinoma cell line which is: 1) activated by vasoactive intestinal polypeptide, or other agents which induce or mimic cAMP; 2) independent of extracellular Na+ or K+; 3) refractory to inhibition by 0.1 mM bumetanide and 1 mM 4-acetamido-4'-isothiocyanostilbene-2,-2'-disulfonic acid; 4) competitively inhibited by NO3-, I-, SCN-, and Br-; 5) inhibited in a noncompetitive-complex manner by the putative Cl- channel-blocking agent, N-phenylanthranilic acid; and 6) localized to the apical membrane of confluent monolayers. This Cl- transport system is, therefore, distinct from the bumetanide-sensitive, basolateral membrane-localized, Na+, K+, Cl- cotransport system previously described in these cells (Dharmsathaphorn, K., Mandel, K., Masui, H., and McRoberts, J.A. (1985) J. Clin. Invest. 75, 462-471). Kinetic studies revealed that Cl- transport by this pathway fit simple Michaelis-Menten kinetics with an apparent Km for Cl- of about 6 mM. Activation by vasoactive intestinal polypeptide increased the Vmax but did not alter the apparent Km. We discuss the possibility that this transport system is a Cl- channel which is intimately involved in hormonally mediated, electrogenic Cl- secretion across T84 cell monolayers.

Synergistic action of cyclic adenosine monophosphate- and calcium-mediated chloride secretion in a colonic epithelial cell line.

Vasoactive intestinal polypeptide (VIP) and the calcium ionophore A23187 caused dose-dependent changes in the potential difference and the short circuit current (Isc) across confluent T84 cell monolayers mounted in modified Ussing chambers. Both VIP and A23187 stimulated net chloride secretion without altering sodium transport. Net chloride secretion accounted for the increase in Isc. When A23187 was tested in combination with VIP, net chloride secretion was significantly greater than predicted from the calculated sum of their individual responses indicating a synergistic effect. VIP increased cellular cyclic AMP (cAMP) production in a dose-dependent manner, whereas A23187 had no effect on cellular cAMP. We then determined whether VIP and A23187 activated different transport pathways. Earlier studies suggest that VIP activates a basolaterally localized, barium-sensitive potassium channel as well as an apically localized chloride conductance pathway. In this study, stimulation of basolateral membrane potassium efflux by A23187 was documented by preloading the monolayers with 86Rb+. Stimulation of potassium efflux by A23187 was additive to the VIP-stimulated potassium efflux. By itself, 0.3 microM A23187 did not alter transepithelial chloride permeability, and its stimulation of basolateral membrane potassium efflux caused only a relatively small amount of chloride secretion. However, in the presence of an increased transepithelial chloride permeability induced by VIP, the effectiveness of A23187 on chloride secretion was greatly augmented. Our studies suggest that cAMP and calcium each activate basolateral potassium channels, but cAMP also activates an apically localized chloride channel. Synergism results from cooperative interaction of potassium channels and the chloride channel.

Vasoactive intestinal polypeptide-induced chloride secretion by a colonic epithelial cell line. Direct participation of a basolaterally localized Na+,K+,Cl- cotransport system.

We have used a well-differentiated human colonic cell line, the T84 cell line, as a model system to study the pathways of cellular ion transport involved in vasoactive intestinal polypeptide (VIP)-induced chloride secretion. A modified Ussing chamber was used to study transepithelial Na+ and Cl- fluxes across confluent monolayer cultures of the T84 cells grown on permeable supports. In a manner analogous to isolated intestine, the addition of VIP caused an increase of net Cl- secretion which accounted for the increase in short circuit current (Isc). The effect of VIP on Isc was dose dependent with a threshold stimulation at 10(-10) M VIP, and a maximal effect at 10(-8) M. Bumetanide prevented or reversed the response to VIP. Inhibition by bumetanide occurred promptly when it was added to the serosal, but not to the mucosal bathing media. Ion replacement studies demonstrated that the response to VIP required the simultaneous presence of Na+, K+, and Cl- in the serosal media. Utilizing cellular ion uptake techniques, we describe an interdependence of bumetanide-sensitive 22Na+, 86Rb+, and 36Cl- uptake, which is indicative of a Na+,K+,Cl- cotransport system in this cell line. This transport pathway was localized to the basolateral membrane. Extrapolated initial velocities of uptake for each of the three ions was consistent with the electroneutral cotransport of 1 Na+:1 K+ (Rb+):2 Cl-. Our findings indicate that VIP-induced Cl- secretion intimately involves a bumetanide-sensitive Na+,K+,Cl- cotransport system which is functionally localized to the basolateral membrane.

Deprival of nicotinamide leads to enhanced glucose transport in chick embryo fibroblasts.

Chick embryo fibroblasts growing in medium free of pyridine ring precursors of NADH and NADPH replicate several times before multiplication ceases. The rate of glucose transport is progressively enhanced, finally reaching levels several times higher than those normally observed in cells severely depleted of NADH. Whereas normal cells respond to additional glucose by further reducing transport, the NADH-depleted cell is refractory to glucose even at five times the normal glucose concentration. Readdition of nicotinamide does little to restore normal transport within 24 h. On the other hand NAD+ or NADP+ provided simultaneously with glucose results in a sharp decline in measurable transport within 2-4 h. The role of the pyridine nucleotides in this reduction of transport function is for the moment unknown.

A human colonic tumor cell line that maintains vectorial electrolyte transport.

A human colonic epithelial cell line, T84, derived from a colonic carcinoma, has been examined both morphologically and functionally. The cells grew to confluence as a monolayer with the basolateral membrane attached to the surface of the culture dish and a microvillus-studded apical membrane facing the media. Tight junctions and desmosomes were demonstrated between adjacent cells. Confluent monolayer cultures conducted vectorial electrolyte transport that could be altered by a variety of secretagogues and antisecretagogues similar to isolated intestinal tissues. This cell line will serve as an excellent model system for the study of electrolyte transport processes and their regulation by peptide hormones and neurotransmitters.

Hexose transport derepressed and refractory to purine regulation in NAD(H)-Depleted Nil cells.

Nil hamster fibroblasts depleted of NAD(H) by growth in medium devoid of nicotinamide (NAm-MEM) exhibit up to 2-3-fold higher rates of glucose transport. Derepression of glucose transport is observed only when Nil cells have become severely depleted of both intracellular NAD(H) and ATP, despite the continued presence of 5.5 mM D-glucose in the growth medium. Neither the initial rate of transport, approximated from 3-O-methylglucose uptake, nor accumulation of D-glucose itself is repressed upon restoring nicotinamide to the medium. Exposure of the cells to NAD+ (10(-5) M), however, leads to a sharp curtailment of transport within 2 to 3 hours. The purines, hypoxanthine and guanine, that sharply reduce glucose transport capacity of normal cells, have no significant effect upon transport activity of NAD(H)-depleted cells.

Effects of structure-activity relationships of alpha-adrenergic compounds on electrolyte transport in the rabbit ileum and rat colon.

Clonidine, an alpha 2-adrenergic agonist, increases electrolyte absorption in the intestine and inhibits diarrhea. In an attempt to develop a gut-specific alpha 2-adrenergic compound for the treatment of diarrhea, we tested several imidazoline derivatives to determine which aspects of the molecule are gut specific. The potency of each compound in the stimulation of electrolyte transport in the rabbit ileum and rat colon was determined using a modified Ussing chamber technique. These results were then compared with the ability of these drugs to lower blood pressure following intracisternal injection in spontaneously hypertensive rats, as well as with other alpha 2-adrenergic properties that have been defined in previous studies. Results indicate that all imidazoline derivatives interact with alpha 2-adrenergic receptors in the gut preparation but activate the ion transport processes to a variable extent; i.e., all analogs tested are either agonist or antagonist for ion transport. Structure activity relationships were derived; for the agonist property in the gut, the imidazoline derivative required (a) substitution (in order of potency) with halide greater than CH3 or C2H5 greater than CH3O or greater than OH at position 2 or 6 of the phenyl ring, or a simultaneous substitution at positions 3 and 4 with hydroxy groups, or certain other groups that independently enhance the agonist properties and (b) the presence of a proper bridging unit between the phenyl and imidazoline rings, NH greater than or equal to CH2. In addition, it was found that certain compounds with a methoxy substitution of the phenyl ring displayed a dissociation between the intestinal ion transport potency and central hypotensive activities. 2-Methoxytolazoline, which was relatively active in the gut as compared with other methoxy-substituted compounds, had little effect in lowering blood pressure. However, 3,5- or 2,5-dimethoxytolazoline had no effect on intestinal ion transport but lowered blood pressure in spontaneous hypertensive rats. These results indicate that the alpha 2-adrenergic receptors in the gut and brain may be different. Further modification of the imidazoline molecule could result in analogs with selective ion transport action in the intestine.