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Irritable Bowel Syndrome Dr T. Ghafghazi Professor of Pharmacology Isfahan university of Medical Sciences and a Member of Goldaru Scientific Department Irritable Bowel Syndrome Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder with a range of symptoms that significantly affect quality of life for patients. The difficulty of differential diagnosis and its treatment may significantly delay initiation of optimal therapy. I. B. S. Assessment IBS associated with: abdominal discomfort Bloating constipation IBS is defined as “abdominal pain or discomfort that occurs in association with altered bowel habits over a period of at least three months.”1 Symptoms of IBS include abdominal pain, change in bowel habits (diarrhea or constipation), bloating, and incomplete defecation.2 However, symptom presentation and severity vary.3 Since current diagnostic criteria are based on symptoms,1 definitive diagnosis of IBS presents challenges due to overlap in symptom presentations with other diseases or associated conditions (e.g., lactose intolerance, inflammatory bowel disease, celiac sprue, small intestinal bacterial overgrowth). Lack of definitive diagnosis and treatment and the chronic, debilitating nature of IBS often compel patients to change or limit their diets,2 seek non-prescribed pharmacological regimens (complementary and alternative medicine [CAM] therapies in particular), and modify routine daily activities in order to manage Symptoms. Pathogenesis and Pathophysiology The pathophysiology of IBS is distinguishable from celiac disease and inflammatory bowel diseases (e.g., ulcerative colitis, Crohn’s disease) since IBS does not present with gross organic or biochemical abnormalities. Although the pathogenesis of IBS is not known, a multi-factorial involvement of diet, gene mutations, psychosocial factors, and immunemediated processes is hypothesized. The contribution of these factors varies and in many cases no single cause can be determined. One theory regarding the pathophysiology of IBS involves interference of neurotransmission between the central nervous system (CNS) and the intestines. A number of structures in the CNS are connected with the gut via serotonergic and cholinergic nerves – referred to as the enteric nervous system (ENS). Independent of the afferent connections, the intestine uses serotonin itself to regulate gut motility. Serotonin binds to 5-HT4 and 5-HT3 receptors, and its signaling activity is terminated by binding to the specific serotonin reuptake transporter. It has been shown that the activity of this transporter is reduced in several GI disorders (including IBS) that present with common symptoms of dysregulated intestinal motility caused by persistent serotonin release at its respective receptors. What is Irritable Bowel Syndrome(IBS)? A group of functional bowel disorders Chronic abdominal complaints without a structural or biochemical cause Constitutes a major health problem with gastrointestinal (GI) symptoms The cause of IBS is unknown. Affects up to ~20 % adults in the industrialized world The condition is more frequent in women. Symptoms of IBS Abdominal discomfort and pain Bloating, mucous in stools, diarrhea, constipation, or alternating diarrhea and constipation Depression, anxiety or stress IBS can be subdivided into Diarrhea-predominant (IBS-D) Constipation-predominant (IBS-C) Alternating diarrhea and constipation Less common symptoms include: feeling sick, headache, belching, poor appetite, feeling quickly 'full' after eating, heartburn, and bladder symptoms (an associated 'irritable bladder'). Some people have occasional mild symptoms. Others have unpleasant symptoms for long periods. Many people fall somewhere in between, with flare-ups of symptoms from time to time. IBS is common and can affect anyone at any age. The cause of IBS is not known. There is no test that confirms the diagnosis of IBS. A doctor will usually diagnose IBS from the typical symptoms. Stress and anxiety can trigger symptoms, or make them worse. Some people have found such things as relaxation techniques, stress counselling, cognitive behaviour therapy, psychotherapy, and similar therapies useful in controlling symptoms of IBS. Serotonin is important in gut function GI disorders may be related to an imbalance of serotonin in the gut an improper reaction of the digestive system to serotonin a faulty communication network between serotonin in the gut and the brain and spinal cord. Serotonin plays a major role in modulating intestinal movement and perception of pain. Helps to soften stools by releasing water. Serotonin (5-hydroxytryptamine, 5HT) A monoamine neurotransmitter Found in cardiovascular tissue, the peripheral nervous system, blood cells, and the CNS HO 95 % resides in the GI tract Serotonergic neurons secrete 5HT The function of serotonin is exerted upon its interaction with specific receptors. 14 distinct families of 5HTreceptors; 5HT1, 5HT2, 5HT3 and …. NH2 N H 5HT3 receptors and its antagonists 5HT3 receptors A ligand-gated cation channel Present in the GI tract Control sensation, contraction of intestinal muscle Release of fluid into the intestines 5HT3 antagonists Slow intestinal transit Decrease intestinal secretions Decrease the water content of stool Diminish colonic pain 5HT4 receptors and its agonists 5HT4 receptors G-protein-coupled receptor Present in the GI tract Mediate both relaxation and contraction of circular smooth-muscle strips Induces small bowel and to a lesser extent colonic fluid secretion 5HT4 agonists Accelerate gastric emptying Accelerate small and large bowel transit Increase stool water content Treatment The goal of current standard pharmacological treatment is to alleviate clinical symptoms of IBS. Because conventional treatments typically do not get to the root of the problem or provide anything but symptomatic relief, patients often seek CAM therapies, including cognitive-behavioral therapy, herbal therapies, probiotics, mind-body therapies, acupuncture, dietary changes, and exercise. Iberogast Drop,Iberogol Drop Composition: contains ethanolic extracts of bitter candytuft(Iberis amara),being the mostimportant, The other ingredients are angelica root()سنبل ختایی,chamomile flowers)(بابونه,carawayfruit )(زیرهmary thistle )(خارمریمbalm leaves )(بادرنجبویهpepperment leaves( )نعناع فلفلیGreater celandine ()مامیرانand liquorice roots))شیر ین بیان The active ingredients are extracts from: Iberis amara, fresh whole plant (bitter candytuft, blomsteriberis)flanonoides, cucurbitacins Angelica archangelica, dried root (angelica, kvanne)furanocoumarins Matricaria recutita, dried flower (matricaria, kamomill)bisabolol Carum carvi, dried fruit (caraway, kummin)polysaccharides Silybum marianum, dried fruit (milk thistle, mariatistel)flavonoides Melissa officinalis, dried leaves (melissa, citronmeliss)rosmarinic acid Mentha piperita, dried leaves (peppermint, pepparmynta)menthol Chelidonium majus, dried herb (greater celandine, skelört)flavonoides Glycyrrhiza glabra, dried root (liquorice, lakritsrot)flavonoides Pharmacological Actions Binding to serotonin receptors was shown for the active substances in Iberogast and for the individual crude drugs Chelidonium majus herba, Matricaria recutita flos, and to a lesser extent Iberis amara herba recens, Mentha piperita folium and Angelica silvestris radix. Binding to muscarine M3 receptors was demonstrated for Iberogast and for the individual drugs Chelidonium majus herba, Iberis amara herba recens, and Angelica archangelica radix. Acid Production Inhibition of acid production, as demonstrated with isolated and enriched guinea pig parietal cells, has been shown for Iberogast and for the individual crude drugs Iberis amara herba recens, Matricaria recutita flos, Mentha piperita folium, Chelidonium majus herba and Glycyrrhiza glabra radix. Iberogast relaxes isolated stomach wall strips from the regions corpus and fundus in the guinea pig. On the antrum region an increase in phasic activity was demonstrated. The individual crude drugs had different activities on the motility of the stomach wall regions. Iberis amara herba recens increased the tonic and phasic activity in all three regions, whereas Chelidonium majus herba had an increasing effect only in the antrum region. Angelica archangelica radix had a relaxing effect in the fundus area. Iberogast acts tonicising on relaxed ileum and relaxing on contracted ileum. Anti-ulcerogenic effect measured as effects on prostaglandin E2 and leukotriene levels in the gastric mucosa has been demonstrated for Iberogast and for Iberis amara herba recens, Carum carvi fructus, Angelica archangelica radix, Mentha piperita folium, Glycyrrhiza glabra radix and Matricaria recutita flos. Anibacterial Effect Antibacterial activity on Helicobacter pylori was exerted by Iberogast. Angelica archangelica radix, Chelidonium majus herba, Matricaria recutita flos, Mentha piperita folium, Melissa officinalis folium and Glycyrrhiza glabra radix all contributed to this effect. It has been shown that each of the 9 crude drugs contained in Iberogast is of importance for the overall effect. The pharmacological Effects of Iberogast IBEROGAST—a safe and effective standard in the treatment of functional gastrointestinal disorders Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are frequent disorders affecting quality of life. They often require long-term treatment. Abdominal symptoms of both disorders can overlap, making differential diagnosis and treatment challenging. The extracts of the herbal combination preparation (Iberogast) exert pharmacological effects in different gastrointestinal regions and can address symptoms of both FD and IBS. The multi-herbal drug (Iberogast) has prosecretory action in the human intestine There is growing evidence that (Iberogast, fixed combination of hydroethanolic herbal extracts), besides being effective in functional dyspepsia, also improves symptoms in irritable bowel syndrome (IBS).. Clinical data indicate that modulation of mucosal secretion is a promising approach to treat intestinal disorders associated with IBS Iberogast Due to the 5-lipoxygenase inhibition the drug can exert anti-inflammatory effects.It also exhibits an antibacterial effect, as is able to inhibit the growth of certain disease-causing bacteria, such as Helicobacter pylori several subspecies, and other pathogenic intestinal inhabitants.There is also a carminative action for Iberogast. Clown’s mustard (Iberis amara) (a.k.a. wild or bitter candytuft) is believed to contain the most active components (Glucosinolates and cucurbitacins) in having specific actions on GI tract tone - although components in its other herbs also play a role: Clown's mustard seems to increase slow wave frequency and amplitude in the small intestine - which causes peristaltic movement. Its extract has a long history of use for normalizing tension and spasms in the gastrointestinal tract and relieving heartburn. It reduces inflammation, triggers fullness and reduces discomfort in the upper abdomen. Iberogast has been studied in over 15 clinical studies. The results from all of the studies indicate that > 80% of people with IBS, GERD, Non-ulcer dyspepsia (NUD) and drug-induced dyspepsia will experience significant relief without side effect. The extracts of the herbal combination preparation (Iberogast) exert pharmacological effects in different gastrointestinal regions. Safety and efficacy data of 12 clinical trials using this drug in FD and IBS since 1990 were evaluated . Double-blind and randomized studies versus placebo or active control found statistically significant effects on patients’ symptoms with a comparable efficacy to a standard prokinetic. Non-interventional and retrospective studies confirmed these effects. IBEROGAST , placebo or cisapride. One placebo controlled study (308 patients) was conducted over a treatment period of eight weeks. In the placebo controlled studies, IBEROGAST showed a significantly superior efficacy vs. placebo for the main outcome criterion. In the study versus Cisapride, an equivalent efficacy for IBEROGAST Was determined Results suggest that Iberogast is a secretogogue in the human intestine by direct epithelial actions and through activation of enteric neurons. The prosecretory effect is due to increased epithelial Cl− fluxes via Cadependent ClCa channels. Iberogol may be a novel option to treat secretory disorders associated with IBS and constipation. 1. 2. 3. 4. Four main mechanisms have been identified: Stimulation of digestive secretions - through interactions with the bitter receptors on the taste buds of the tongue. Regulation of peristalsis (the rhythmic contraction of the intestines) - by exerting either a relaxing or stimulating effect on the intestinal smooth muscle. Protecting the lining of the stomach and intestines - by stimulating the production of mucus by mast cells (mucus-producing cells of the stomach and intestines) as well as preventing the formation of inflammatory substances within the intestinal tract. Prevention of excessive flatulence - by reducing the formation of intestinal gases. Iberogast has been very successfully used to treat IBS and other GI diseases – for several years in Germany Ammon, H., P. et al. Spasmolytic and tonic effect of Iberogast in intestinal smooth muscle. Phytomedicine. 13 Suppl 5: 67-74, 2006 Arnim, U. et al.Iberogasta phytopharmacon for patients with functional dyspepsia: results of a multicenter, placebo-controlled double-blind study. Am J Gastroenterol. 102 (6): 1268-75, 2007 -In one study , 20 patients diagnosed with chronic functional disorders for 1- 20 years were given Iberogast for 3 to 32 days – Patients also stopped taking medications ( E.g. antacids, anti-spasmodic agents, motility inducing substances) used to treat abdomenal pressure/pain, belching, heartburn, vomiting, nausea, fullness, lack of appetite, constipation, and diarrhea. Abdominal pressure and pain - was the most common experienced symptom, with 11 of the patients rating it as severe. After 6 days of treatment, only 6 of the patients continued to rate their abdominal pain and pressure as severe. After 2 weeks, this symptom had completely resolved for 16 patients. √ Diarrhea - rated as severe in five of the patients, but after 2 weeks, only one patient continued to have moderate diarrhea. . Anti-Emetic Effect of Iberogast The previously reported anti-emetic effects of Iberogast were studied objectively in a clinical study of 18 inpatients aged between 32 and 84 years. Most had severe underlying disorders characterized by moderate to marked nausea. Patients received the recommended dose of 20 drops 3 times a day for up to 14 days. A clear effect was observed after two days' treatment. After 5 days' treatment there was no further vomiting or nausea, except in one patient who had some residual symptoms. The experience of previous studies--that Iberogast is extremely well tolerated--was confirmed Contraindications IBEROGAST must not be taken in case of known allergies to the active ingredients Patients with pre-existing liver disease should consult their doctor prior to commencing Pregnancy and lactation From a toxicological perspective no evidence of concern regarding the administration of IBEROGAST during pregnancy and lactation can be determined from the available data on reproductive toxicity (embryotoxicity, teratogenicity, peri- and postnatal toxicity). Interactions with other medicinal products No interactions were known at the time of printing. Adverse Reactions : In very rare cases, less than one in 10,000, hypersensitivity reactions such as exanthema, pruritus and dyspnea could occuring. Toxicology Product-specific investigations of single-dose and repeat-dose toxicity have shown a very low toxicity forIberogast . In vivo genotoxicity studies on the productspecific extract have been performed. No genotoxicity could be found for Iberogol in the tests performed. Nor are there any reports in the literature of genotoxicity for the individual crude drugs Extensive investigations with IBEROGAST in two animal species were performed assessing acute, subchronic and chronic toxicity at 3 and 6 months, in the areas of reproductive toxicity, fertility, embryonic, pre-and post-natal development and mutagenicity. There is no evidence for any acute or chronic-toxic, reproductive - or embryo-toxic potentials, even when doses of up to 1200 times the recommended daily dose were tested. Various studies evaluated the tolerability profile of this preparation: the incidence of adverse drug reactions was 0.04 %. The worldwide spontaneous reporting system confirmed this profile. It has a favorable tolerability which is relevant for long-term treatment. Dosage and Administration Unless otherwise prescribed, IBEROGAST is taken before or with meals in some liquid as following: Adults and children over 12 years Take 20 drops 3 times a day (1.0 mL) Children 6 to 12 years Give 15 drops 3 times a day (0.75 mL) Children 3 to 6 years Give 10 drops 3 times a day (0.5 mL) Children 3 months to 3 years Give 8 drops 3 times a day (0.4 mL) Children under 3 months Give 6 drops 3 times a day (0.3 mL) Duration of use depends on the kind, severity and course of the disease. Shake the bottle before use. Overdose In acute oral toxicity testing of IBEROGAST in various animal species and during longterm therapeutic experience in humans, no toxic signs of overdose were observed.