Carmelo Scarpignato

Myths and Misconceptions About Chronic Constipation

There are many strongly held beliefs about constipation that are not evidence based. The purpose of this review is to address these beliefs concerning various aspects of constipation. There is no evidence to support the theory that diseases may arise via “autointoxication,” whereby poisonous substances from stools within the colon are absorbed. Dolichocolon, defined as an elongated colon, should not be seen as a cause of constipation. The role of sex hormones altering gut function during the menstrual cycle appears to be minimal. During pregnancy they may play a role in slowing gut transit. Hypothyroidism can cause constipation, but among patients presenting with constipation, hypothyroidism is rare. A diet poor in fiber should not be assumed to be the cause of chronic constipation. Some patients may be helped by a fiber-rich diet but many patients with more severe constipation get worse symptoms when increasing dietary fiber intake. There is no evidence that constipation can successfully be treated by increasing fluid intake unless there is evidence of dehydration. In the elderly constipation may correlate with decreased physical activity, but many cofactors are likely to play a role. Intervention programs to increase physical activity as part of a broad rehabilitation program may help. It is unlikely that stimulant laxatives at recommended doses are harmful to the colon. A proportion of patients with chronic constipation is dependent of laxatives to achieve satisfactory bowel function, but this is not the result of prior laxative intake. Tolerance to stimulant laxatives is uncommon. There is no indication for the occurrence of “rebound constipation” after stopping laxative intake. While laxatives may be misused, there is no potential for addiction.

The burden of constipation on quality of life: results of a multinational survey

Background The impact of constipation on quality of life (QoL) may vary in different cultural or national settings.

Global eradication rates for Helicobacter pylori infection: systematic review and meta-analysis of sequential therapy

Objective To do a systematic review and meta-analysis of studies comparing sequential therapy for eradication of Helicobacter pylori with pre-existing and new therapies, thus providing a glimpse of eradication success worldwide. Design Systematic review and meta-analysis. Data sources Medline, Embase, and Cochrane Central Register of Controlled Trials up to May 2013; abstract books of major European, American, and Asian gastroenterological meetings. Study selection Randomised controlled trials in previously untreated adults, in which sequential therapy was compared with a pre-existing or new therapy. Results 46 randomised controlled trials were reviewed and analysed. 5666 patients were randomised to sequential therapy and 7866 to other (established and new) treatments. The overall eradication rate of sequential therapy was 84.3% (95% confidence interval 82.1% to 86.4%). Sequential therapy was superior to seven day triple therapy (relative risk 1.21, 95% confidence interval 1.17 to 1.25; I2=29.3%; number needed to treat 6 , 95% confidence interval 5% to 7%), marginally superior to 10 day triple therapy (1.11, 1.04 to 1.19; I2= 67.2%; NNT 10, 7 to 15), but not superior to 14 day triple therapy (1.00, 0.94 to 1.06; I2=54.3%), bismuth based therapy (1.01, 0.95 to 1.06; I2=21.1%), and non-bismuth based therapy (0.99, 0.94 to 1.05; I2=52.3%). Data on eradication according to pre-treatment antimicrobial susceptibility testing were available in eight studies, and sequential therapy was able to eradicate 72.8% (61.6% to 82.8%) of the strains resistant to clarithromycin. Conclusions Eradication rates with pre-existing and new therapies for H pylori are suboptimal. Regional monitoring of resistance rates should help to guide treatment, and new agents for treatment need to be developed.

Rifaximin, a poorly absorbed antibiotic: pharmacology and clinical potential.

Rifaximin (4-deoxy-4′-methylpyrido[1′,2′-1,2]imidazo- [5,4-c]-rifamycin SV) is a synthetic antibiotic designed to modify the parent compound, rifamycin, in order to achieve low gastrointestinal (GI) absorption while retaining good antibacterial activity. Both experimental and clinical pharmacology clearly show that this compound is a nonsystemic antibiotic with a broad spectrum of antibacterial action covering Gram-positive and Gram-negative organisms, both aerobes and anaerobes. Being virtually nonabsorbed, its bioavailability within the GI tract is rather high with intraluminal and fecal drug concentrations that largely exceed the minimal inhibitory concentration values observed in vitro against a wide range of pathogenic organisms. The GI tract represents, therefore, the primary therapeutic target and GI infections the main indication. The appreciation of the pathogenic role of gut bacteria in several organic and functional GI diseases has increasingly broadened its clinical use, which is now extended to hepatic encephalopathy, small intestine bacterial overgrowth, inflammatory bowel disease and colonic diverticular disease. Potential indications include the irritable bowel syndrome and chronic constipation, Clostridium difficile infection and bowel preparation before colorectal surgery. Because of its antibacterial activity against the microorganism and the lack of strains with primary resistance, some preliminary studies have explored the rifaximin potential for Helicobacter pylori eradication. Oral administration of this drug, by getting rid of enteric bacteria, could also be employed to achieve selective bowel decontamination in acute pancreatitis, liver cirrhosis (thus preventing spontaneous bacterial peritonitis) and nonsteroidal anti-inflammatory drug (NSAID) use (lessening in that way NSAID enteropathy). This antibiotic has, therefore, little value outside the enteric area and this will minimize both antimicrobial resistance and systemic adverse events. Indeed, the drug proved to be safe in all patient populations, including young children. Although rifaximin has stood the test of time, it still attracts the attention of both basic scientists and clinicians. As a matter of fact, with the advancement of the knowledge on microbial-gut interactions in health and disease novel indications and new drug regimens are being explored. Besides widening the clinical use, the research on rifaximin is also focused on the synthesis of new derivatives and on the development of original formulations designed to expand the spectrum of its clinical use.

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.

Proton pump inhibitors in GORD: An overview of their pharmacology, efficacy and safety

Gastric acid secretion is a complex phenomenon under nervous and hormonal influence. The stimulation of proton pump (H(+), K(+)-ATPase) in the parietal cell represents the final step of acid secretion and this knowledge has led to the development of a class of drugs, the proton pump inhibitors (PPIs), which are targeted at blocking this enzyme. Chemically, all the available PPIs consist of a benzimidazole ring and a pyridine ring, but vary in the specific side ring substitution. As a class, they are the most potent inhibitors of gastric acid secretion available. Although there are differences among PPIs concerning their pharmacokinetics, pharmacodynamics, influence by food and antacids as well as potential for drug interactions, it is not always evident whether these often subtle differences are clinically relevant. A careful evaluation of the available studies reveals that rabeprazole and esomeprazole achieve more rapid acid inhibition than other PPIs. Also, the effect of rabeprazole is less dependent upon genetic make-up than all other PPIs, giving rise to less inter-subject variability and leading to a more predictable effect. Esomeprazole, by inhibiting its own catabolism, makes all patients slow metabolizers, but could expose them to potential drug interactions. PPIs are the mainstay of medical treatment of gastro-oesophageal reflux disease (GORD), in that they are able to provide 80-85% healing rate of oesophageal lesions, including ulcers, and to reduce the incidence of complications like strictures as well as dysplasia and adenocarcinoma in Barretts oesophagus (BO). Also relief of symptoms can be achieved in about 80% of cases, even though this benefit is reduced by a factor of approximately 20% in patients with non-erosive reflux disease (NERD). Their effect on Barretts oesophagus and the extra-oesophageal manifestations of GORD is much less consistent. In general, the tolerability profile of PPIs is good in both short- and long-term clinical trials. This safety profile is similar across the various PPIs used in clinical practice and is extended to children and pregnant women, where they do not present any major teratogenic risk.

Caustic injury of the upper gastrointestinal tract: A comprehensive review

Prevention has a paramount role in reducing the incidence of corrosive ingestion especially in children, yet this goal is far from being reached in developing countries, where such injuries are largely unreported and their true prevalence simply cannot be extrapolated from random articles or personal experience. The specific pathophysiologic mechanisms are becoming better understood and may have a role in the future management and prevention of long-term consequences, such as esophageal strictures. Whereas the mainstay of diagnosis is considered upper gastrointestinal endoscopy, computed tomography and ultrasound are gaining a more significant role, especially in addressing the need for emergency surgery, whose morbidity and mortality remains high even in the best hands. The need to perform emergency surgery has a persistent long-term negative impact both on survival and functional outcome. Medical or endoscopic prevention of stricture is debatable, yet esophageal stents, absorbable or not, show promising data. Dilatation is the first therapeutic option for strictures and bougies should be considered especially for long, multiple and tortuous narrowing. It is crucial to avoid malnutrition, especially in developing countries where management strategies are influenced by malnutrition and poor clinical conditions. Late reconstructive surgery, mainly using colon transposition, offers the best results in referral centers, either in children or adults, but such a difficult surgical procedure is often unavailable in developing countries. Possible late development of esophageal cancer, though probably overemphasized, entails careful and long-term endoscopic screening.

Endogenous cholecystokinin in postprandial lower esophageal sphincter function and fundic tone in humans

Transient lower esophageal sphincter (LES) relaxations (TLESRs) are the main underlying mechanism of gastroesophageal reflux. Although CCK acts through CCK-A receptors to increase the TLESRs induced by gastric distension, the respective roles of endogenous CCK and fundic tone in triggering postprandial TLESRs remain unknown. The aim of this study was to determine the effect of the CCK-A receptor antagonist, loxiglumide, on postprandial LES function and fundic tone in humans. LES motor events and fundic tone were simultaneously monitored in two groups of healthy volunteers. Recordings were performed during fasting and for 3 h after a liquid meal (200 ml/200 kcal) administered either orally or intraduodenally at a rate mimicking gastric emptying. Each subject received loxiglumide (10 mg. kg-1. h-1) or saline (control) in randomized order, which was started 40 min before the meal and maintained for 3 h thereafter. After the oral meal, loxiglumide significantly reduced TLESRs (P = 0.002) without significantly affecting LES pressure and fundic tone. After duodenal infusion of the meal, loxiglumide totally abolished the increase in TLESRs, reduced LES pressure fall (P < 0.02), and strongly inhibited fundic relaxation (P = 0.0001). We concluded that endogenous CCK is involved in the postprandial control of both LES function and fundic tone through activation of CCK-A receptors.Transient lower esophageal sphincter (LES) relaxations (TLESRs) are the main underlying mechanism of gastroesophageal reflux. Although CCK acts through CCK-A receptors to increase the TLESRs induced by gastric distension, the respective roles of endogenous CCK and fundic tone in triggering postprandial TLESRs remain unknown. The aim of this study was to determine the effect of the CCK-A receptor antagonist, loxiglumide, on postprandial LES function and fundic tone in humans. LES motor events and fundic tone were simultaneously monitored in two groups of healthy volunteers. Recordings were performed during fasting and for 3 h after a liquid meal (200 ml/200 kcal) administered either orally or intraduodenally at a rate mimicking gastric emptying. Each subject received loxiglumide (10 mg ⋅ kg-1 ⋅ h-1) or saline (control) in randomized order, which was started 40 min before the meal and maintained for 3 h thereafter. After the oral meal, loxiglumide significantly reduced TLESRs ( P = 0.002) without significantly affecting LES pressure and fundic tone. After duodenal infusion of the meal, loxiglumide totally abolished the increase in TLESRs, reduced LES pressure fall ( P < 0.02), and strongly inhibited fundic relaxation ( P = 0.0001). We concluded that endogenous CCK is involved in the postprandial control of both LES function and fundic tone through activation of CCK-A receptors.

Experimental and Clinical Pharmacology of Rifaximin, a Gastrointestinal Selective Antibiotic

Rifaximin (4-deoxy-4′-methylpyrido[1′,2′-1,2]imidazo [5,4-c]rifamycin SV) is a product of synthesis experiments designed to modify the parent compound, rifamycin, in order to achieve low gastrointestinal (GI) absorption while retaining good antibacterial activity. Both experimental and clinical pharmacology clearly show that this compound is a non-systemic antibiotic with a broad spectrum of antibacterial action covering Gram-positive and Gram-negative organisms, both aerobes and anaerobes. Being virtually non-absorbed, its bioavailability within the GI tract is rather high with intraluminal and fecal drug concentrations that largely exceed the minimum inhibitory concentration values observed in vitro against a wide range of pathogenic organisms. The GI tract represents therefore the primary therapeutic target and GI infections the main indication. This antibiotic has therefore little value outside the enteric area and this will minimize both antimicrobial resistance and systemic adverse events. Indeed, the drug proved to be safe in all patient populations, including young children. The appreciation of the pathogenic role of gut bacteria in several organic and functional GI diseases has increasingly broadened its clinical use, which is now extended to hepatic encephalopathy, small intestine bacterial overgrowth, inflammatory bowel disease and colonic diverticular disease.

DNA/protein flow cytometry as a predictive marker of malignancy in dysplasia-free Barrett's esophagus: Thirteen-year follow-up study on a cohort of patients

Intestinal metaplasia identifies Barretts esophagus (BE) and is associated with an increased risk for esophageal adenocarcinoma. Dysplasia occurs as an intermediate step. However, progression from metaplasia to neoplasia without the demonstration of dysplasia has been described. The role of dual-parameter flow cytometry (FC) as a predictor of neoplastic risk in dysplasia-free cases was evaluated. DNA/protein FC and histology were performed on 362 samples from 30 dysplasia-free BE patients, followed up since 1985 once every 1-2 years. Nine cases were aneuploid, five of which (group IV) were frankly aneuploid; in the other four cases (group III), aneuploidy was detectable by dual-parameter analysis only. Twenty-one patients were diploid. Twelve (group II) also had an abnormally high G1-phase protein content compared to group I (nine patients), which were diploid with a low-moderate protein content. In three patients of group IV an adenocarcinoma in situ was diagnosed, after 5, 6, and 10 years, respectively. In two patients of group III, a low- and a high-grade dysplasia were observed at 3 and 6 years follow-up, respectively. One patient of group I first acquired a high protein content, then an aneuploid DNA content, and then progressed to adenocarcinoma (12 years). None of the still diploid patients (17 cases) have progressed to dysplasia or cancer compared with 6 of 13 presently aneuploid patients (P < 0.01). In conclusion, DNA/protein FC is a marker of increased malignant potential and thus may be used to detect patients at higher risk in dysplasia-free BE and assist in understanding the various stages of malignant transformation in long-term follow-up studies.