Gastrointestinal complaints rank among the most frequent reasons why people seek medical advice. The most common functional gastrointestinal disorders (FGIDs) seen in clinical practice are functional dyspepsia (FD) and irritable bowel syndrome (IBS), characterised by recurrent episodes of gastrointestinal symptoms, in the absence of structural lesions that explain symptoms. While symptoms of epigastric pain, bloating, nausea, belching, early satiety and heartburn are predominant in functional dyspepsia, abdominal discomfort, bloating and disturbed patterns of defecation (constipation, diarrhea or constipation/diarrhea) are common in patients with IBS. FGIDs reduce the health-related quality of life and account for an increased healthcare burden. The pathogenesis of functional gastrointestinal disorders is probably multi-factorial, genetic and environmental factors are thought to contribute to alterations in visceral sensory function, motility, bacterial overgrowth and central nervous system processing. Inflammation is considered a risk factor for the development of both functional dyspepsia and irritable bowel syndrome. Currently, the existing therapies to treat multiple symptoms of FGIDs are suboptimal, associated with restricted therapeutic potential and new agents are awaited that would improve global IBS symptoms. A wide variety of treatments have been used to manage functional gastrointestinal disorders and include Helicobacter pylori eradication, antacids, mucosal protectants, antisecretory agents, prokinetics, antidepressants and visceral analgesics. The fact that no single available therapy consistently provides relief to the majority of the patients validates the heterogeneity of these disorders. The emerging therapies are largely aimed to normalise pain perception and gastrointestinal motor and reflux function.
The therapy of functional gastrointestinal disorders is one of the domains of phytotherapeutic treatments. Traditionally, plants with a high tannin content, showing astringent properties, were particularly valued to treat diarrhea and dysentery whereas bitter, aromatic and bitter-aromatic plants were especially employed to treat gastrointestinal cramps and pain. Investigations on traditionally used plants have resulted in the isolation, and chemical and pharmacological characterisation of many different types of compounds. Most of these agents are helpful to prevent or arrest the progression, rather than to treat disease. Further, they exhibit pleotropic actions and therefore may serve as important leads for developing novel therapies for the treatment of functional gastrointestinal disorders.
So far, relatively few herbal medicines have been evaluated scientifically to prove their safety, potential benefits and effectiveness in gastrointestinal disorders (Table: Experimental studies on traditional herbs used in gastrointestinal disorders). This chapter specifically deals with the evaluation methods for the development of quality herbal medicines intended to be useful in FGIDs.
Functional dyspepsia
Functional dyspepsia is a clinical syndrome, whose origin is unknown, defined by chronic or recurrent pain or discomfort in the upper abdomen. On the basis of the Rome III diagnostic criteria for functional gastrointestinal disorders, patients who suffer from functional dyspepsia in the absence of any organic disease are categorised as having postprandial distress syndrome or epigastric pain syndrome for at least 3 months. About 15-30% of adult patients suffer from various different functional dyspeptic conditions. Several pathophysiological mechanisms are involved in functional dyspepsia, including visceral hypersensitivity, both in the stomach and the duodenum, impaired gastric accommodation, antral overdistention, delayed gastric emptying and abnormal duodenojejunal motility. Induction of gastric hypersensitivity by acid in the stomach seems to be important in a subset of patients. Many drugs can induce dyspepsia as a gastrointestinal side-effect, the major cause being the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for arthritis and chemotherapeutic agents in cancer. Studies also suggest a possible link with G-protein polymorphisms in dyspepsia.
Currently, functional dyspepsia is classified into ulcer-like dyspepsia, dysmotility-like dyspepsia and non-specific dyspepsia, in which symptoms do not clearly fit into any of the above categories. While antacids, H2-receptor antagonists and proton-pump inhibitors are useful in ulcer-like dyspepsia, pro-kinetic agents are more effective in dysmotility-like dyspepsia. Most therapies for patients with functional dyspepsia are intended to normalise pain perception and gastrointestinal motor and reflex function. Serotonin is the key mediator of gut function in relation to gastrointestinal motility, secretion and sensation of pain. There is limited evidence that the 5-hydroxytryptamine 5-HT3 antagonist alosetron has potential efficacy in functional dyspepsia, perhaps via visceral analgesic effects. Animal studies also suggest that acid can induce serotonin release from enterochromaffin cells in the duodenum, which may in turn activate 5-HT3 receptors and alter visceral sensation. Acid in the duodenum can also induce fundic relaxation. Thus, the interaction between acid and 5-HT3 receptor antagonism is of interest in functional dyspepsia. A number of compounds may have visceral analgesic effects in the upper gastrointestinal tract, including 5-HT3 antagonists and 5-HT4 agonists. Approximately 25% of patients with functional dyspepsia have slow gastric emptying, and perhaps 10% have accelerated gastric emptying. It is, therefore, important to avoid the use of prokinetic therapy in patients who have accelerated gastric emptying, as presumably this would worsen symptoms.
No standard therapy is currently available for functional dyspepsia. From ancient times, bitter herbal drugs have played a role in the therapy of patients with dyspeptic symptoms. Studies point out that different plant-derived extracts and their constituents can give gastro/cytoprotection through several mechanisms (Table: Experimental studies on traditional herbs used in gastrointestinal disorders). Flavonoids are highly gastroprotective probably due to enhancement of the release of nitric oxide and neuropeptides, such as calcitonin gene-related peptide, released from sensory afferent nerves, which increase gastric microcirculation. These appear to stimulate, at even very small concentrations, the secretion of the stomach as well as the digestive glands and strengthen the smooth musculature of the digestive tract. Bitter substances are often combined with essential oils, which act primarily as spasmolytics and analgesics and possess anti-Helicobacter pylori effects. They exert anti-inflammatory action by:
Table: Experimental studies on traditional herbs used in gastrointestinal disorders
| Name | Part used | Use | Constituents | Study type | Results |
| STW5 Iberogast® (herbal formula) | Ethanolic extracts of 9 plants | Functional dyspepsia (FD) and irritable bowel syndrome (IBS) | Methionine-like sulphur-compounds | Animal studies | Diminished binding affinity of 5-HT(4), muscarinic M(3), and opioid receptors in vitro |
| Artichoke (Cynara scolymus L.) | Leaf extract | Irritable bowel syndrome (IBS) | Caffeoylquinic acids and flavonoids | Animal studies | Protected animals from gastric ulceration |
| N-095 (crude drug containing red ginseng, polygala root, saffron, antelope horn and aloe wood) | Dried powder | Combat stress | Multi components | Experimental studies in rats | Prevented gastric ulceration — induced by restraint and water-immersion stress |
| Baishouwu (Chinese herbal drug) | Dried root tubers of 3 plants | Gastric diseases | Multicomponents | Experimental studies in rats | Offered gastroprotection against ethanol and indometacin-induced gastric lesions |
| Turmeric (Curcuma longa L.) | Rhizome extract | Ulcer and non-ulcer dyspepsia | Curcumin (diferuloyl methane) | Animal studies in vivo and anti-H. pylori in vitro | Demonstrated antiulcer, anti-inflammatory, anticancer and analgesic effects |
| Peppermint (Mentha piperita L.) | Leaf essential oil | Gastroprotective use | Menthol and menthonin | Animal studies | Antimicrobial, antispasmodic, antioxidant and analgesic effects |
| Anise (Pimpinella anisum L.) | Seed aqueous suspension | Gastroprotective use in Arab medicine | Volatiles | In vivo
experimental ulceration in rats and anti-H.pylori in vitro |
Gastro protection against necrotising agents and indometacin |
| Cardamom (Elettaria cardamomum Maton.) | Crude methanolic extract and fractions | Gastro protective use in Unani medicine | Terpenes and phenolic compounds | Experimental ulceration in rats | Gastro protection against ethanol and aspirin-induced injury |
| Fenugreek (Trigonella foenum graecum) | Aqueous extract of seed and gel fraction | Gastric complaints | Steroidal saponins and alkaloids | Rat study | Prevents ethanol-induced gastric lesions |
| Sangre de grado (Croton urucurana var. genuinus and related species) | Red sap from trunk wood of C urucurana | Gastric ulcer and diarrhoea | Proantocyanidins, taspine | Experimental study in rats and guinea-pigs | Antiulcer, antidiarrhoeal and visceral antinociceptive effects |
| Copaiba oil (Copaifera langs dorffii Desf.) and related species) | Oleo-resin from trunk wood | Gastrointestinal disorders | Volatiles and diterpenes that include kaurenoic acid | In vivo
experimental studies with rats |
Antiulcer, wound healing and anti-inflammatory effects |
| Aroeira (Myracrodruon urundeuva Engl.) | Aqueous extract from stem bark | Traditional use in gastric dyspepsia, anc diarrhoea | Tannins and Chalcones | Experimental studies with rats and guinea-pigs | Gastroprotection against ethanol, stress and histamine-induced lesions; acetic acid-induced colitis |
| Monkey puzzle (Araucaria araucana Mol.) | Resin | Mapuche Amerindian use to treat ulcers | Labdane diterpenes and lignans | Experimental studies with mice | Gastroprotection against ethanol-HCl-induced lesions |
| Macela (Egletes viscosa L.) | Ethanolic extract of flower buds and flavonoid, ternatin | Gastric dyspepsia, diarrhoea and constipation | Volatiles, flavonoid (ternatin) and diterpenes (centipedic acid and 12-acetoxy hawtriwaic acid) | Animal studies | Antiulcer, antidiarrhoeal and anti-inflammatory effects |
| Tsubaki (Camellia japonica L.) | Methanolic extract of flower buds | Blood vomiting and stomach ache | Camelliosides | Experimental studies in rats | Decreased the ethanol and indometacin-evoked gastric ulceration |
| Mango (Mangifera indica L.) | Aqueous decoction of mango flowers | Gastrointestinal disorders and arthralgias | Xanthone (mangiferin), flavonoids and triterpenes | Acute and subacute models of gastric ulceration in rodents | Decreased the acetic acid, ethanol and stress-induced gastric ulceration |
| Grape-seed (Vitis vinifera L.) | Seed extract | Gastro protection | Proanthocyanidins | Animal models of gastric ulceration | Decreased the ethanol, stress, and indometacin-induced gastric ulceration |
| Karela (Momordia charantiaL.) | Dried powdered fruits | Traditionally used in diabetes and for healing of peptic ulcer | Triterpenes and glycosides, karavilagenins and karavilosides | Animal models of gastric ulceration | Reduced ulceration |
| Almecega (Protium heptaphyllum March.) | Resin from the trunk wood | Traditionally used remedy in gastrointestinal disorders | Volatiles and triterpenes (alpha-and beta-amyrin) | Animal studies | Antiulcer, visceral antinociceptive and anti-inflammatory effects of α- and β-amyrin |
| Coptis (Coptis Chinensis Franch.) | Root extract | Traditionally used remedy in gastrointestinal disorders | Alkaloids (10% berberine) | Animal studies | Inhibits ulcer formation and acid secretion |
| Bone setter (Cissus quadrangularis L.) | Methanolic extract | Traditionally used for fracture healing | Vitamin C and β- carotene | Rat study | Prevents indometacin-induced ulceration |
| Red sanders (Pterocarpus santalinus L.) | Ethanolic extract | Traditional herbal drug for wound healing | 3-keto-oleanane | Rat gastric ulceration model in vivo and anti-H. pylori in vitro | Cytoprotection antioxidant, anti-H. pylori and antiulcer effects |
STW 5 is composed of ethanolic extracts from nine plants (Ibera Amara Totalis, Angelicae Radix, Cardui Mariae Fructus, Carvi Fructus, Chelidonii Herba, Liquiritae Radix, Marticariae Flos, Melissae Folium, Menthae Piperitae Folium). N-095 is a mixture of red ginseng, polygala root, saffron, antelope horn and aloe wood.
Sangre de grado is derived from several Croton species (Croton dracanoides, Croton palanostigma, Croton lecheleri, Croton urucurana).
Baishouwu is an appellative name of dried root tubers from three Asdepiadaceae plants: Cynanchum auriculatum Royle ex Wight, Cynanchum bungei Decne and Cynoctonum wilfordii Maxim.
• suppressing the neutrophil/cytokine cascade in the gastrointestinal tract
• promoting tissue repair through expression of various growth factors
• exhibiting antioxidant activity, scavenging reactive oxygen species
• inhibiting cytochome P450 2F1 activity, producing antinecrotic and anticarcinogenic activities.
However, experimental studies have aimed mostly to validate the traditional use of plants in gastrointestinal disease, but no attempt has been made to verify their potential in functional dyspepsia.
Irritable bowel syndrome
IBS is a potentially debilitating condition characterised by abdominal discomfort, bloating, and disturbed patterns of defecation with a lower health-related quality of life. According to Rome III criteria, irritable bowel syndrome is defined as recurrent abdominal pain or discomfort for at least 3 days per month. It affects approximately 15-30% of the general population. The prevalence is equally divided among three subtypes: irritable bowel syndrome with constipation, IBS with diarrhea, and irritable bowel syndrome with alternating constipation/diarrhea.
Conventional therapy includes the use of bulk laxatives and stool softeners for constipation, anti-motility drugs for diarrhea, and antispasmodics, antimuscarinics and antidepressants for pain and spasm. Chronic constipation is a very common disorder, and the goals in treating such patients are to improve the patient’s symptoms and to restore normal bowel function, aiming to achieve at least three bowel movements per week. Serotonin plays a prominent role in chronic constipation, since it affects the intestinal motility, fluid secretion and sensation through activation of receptors present in enterochromaffin cells.
The only FDA-approved agents for chronic idio-pathic constipation are tegaserod (5-HT3 agonist) and lubiprostone, a type 2 chloride-channel activator, which both represent real therapeutic advances in the management of these patients. Lubiprostone draws chloride, sodium, and water into the lumen of the gut enhancing fluid secretion and facilitating increased motility and colonic transit. Lubiprostone, although significantly better than placebo in improving symptoms of constipation severity, stool consistency, straining, and abdominal discomfort, has been shown to be associated with adverse events such as nausea (30.2%), diarrhea (19.2%) and distention (9.3%). However, patients are refractory to these agents in the presence of pelvic floor dyssynergia, leaving the option for therapy with a prokinetic agent, fibre or a laxative. Thus, there is an overall dissatisfaction with traditional treatment options from patients and physicians.
Clinical studies with herbals in functional gastrointestinal disorders
In the recent past, a few controlled clinical studies were carried out with phytotherapeutic combinations (i.e. combinations of various plant/herbal extracts with a number of different active ingredients) which showed superiority over the placebo treatments (Table: Clinical studies with herbal medicinals in gastrointestinal functional disorders). However, randomised controlled trial (RCTs) data supporting the efficacy of these treatments in patients with functional gastrointestinal disorders (FGIDs) are still lacking. RCTs indicated that peppermint oil could be efficacious for symptom relief in irritable bowel syndrome and meta-analysis confirmed this. Placebo-controlled RCTs demonstrated the clinical efficacy and safety of a polyherbal preparation, STW 5 (Iberogast, Enzymatic Therapy Inc.) for the treatment of both functional dyspepsia and patients with irritable bowel syndrome. The pharmacological effects, as well as the therapeutic effectiveness, tolerability, and toxicity, of Iberogast were experimentally and clinically recorded and documented. These studies indicated that Iberogast promotes gastric relaxation and stimulates antral motility. Tong-xie-ning, a standard Chinese traditional herbal formula, and Padma Lax, a Tibetan herbal medicine, showed significant improvement of global symptoms in FGID, when compared with placebo treatment. An RCT assessing artichoke leaf extract in 247 patients with functional dyspepsia demonstrated a significant improvement in both overall symptoms and disease-specific quality of life compared with placebo.
Table: Clinical studies with herbal medicinals in gastrointestinal functional disorders
| Name | Part used | Use | Constituents | Study type | Results |
| STW 5 lberogast® (herbal formula) | Ethanolic extracts of 9 plants | Functional dyspepsia and IBS | Methionine like sulphur-compounds | Placebo-controlled RCT | Improved gastrointestinal symptom-severity score |
| Carmint | Total extracts of 3 plants | Irritable bowel syndrome (IBS) | (E)-2-dodecenal, eugenol, menthol and L-carvone | Pilot clinical study | Reduced the severity and frequency of abdominal pain/ discomfort |
| Tong-xie-ning (TCM-herbal formula) | Dried extract of four herbs | Diarrhoea-predominant IBS | Complex compound containing paeoniflorin | Placebo-controlled RCT | Reduced symptom severity |
| Hange-koboku-to (HKT, Kampoo medicine) | Dried mixture of 5 crude herbs | Functional dyspepsia | Magnorol, konokiol, perillaldehyde, 6-gingerol, 6-shogaol | Open clinical study | Improves delayed gastric emptying (prokinetic effect) |
| Padma Lax (Tibetan herbal medicine) | Dried extract from 10 plants | Constipation-predominant IBS | Multicomponent | Double-blind randomised pilot study | Reduced symptom severity |
| Artichoke (Cynara scolymus L.) | Leaf extract | Dyspepsia and IBS | Caffeoylquinic acids and flavonoids | Open clinical study | Amelioration of global symptoms and improvement in QOL score |
| Peppermint (Mentha piperita L.) | Leaf essential oil | Irritable bowel syndrome (IBS) | Menthol and menthonin | Double-blind RCT | Smooth muscle relaxation; analgesia |
| Turmeric (Curcuma longa L.) | Rhizome extract | IBS; ulcer and non-ulcer dyspepsia | Curcumin (diferuloyl methane) | Placebo-controlled RCT | Improved healing of peptic ulcer and of non-ulcer dyspepsia but not of IBS |
| Red pepper (Capsicum annuum ssp.) | Powder | Functional dyspepsia | Capsaicin | Placebo-controlled RCT | 60% Reduction of symptom score |
| Mangava-brava (Lafoensiapacari St Hil.) | Methanolic extract | Used in gastric ulcer and inflammatory conditions | Ellagic acid | Double-blind RCT against H. pylori | Well tolerated and patients were symptom-free in an 8-week trial |
STW 5 is composed of ethanolic extracts from nine plants (Ibera AmaraTotalis, Angelicae Radix, Cardui Mariae Fructus, Carvi Fructus, Chelidonii Herba, Liquiritae Radix, Marticariae Flos, Melissae Folium, Menthae Piperitae Folium).
Carmint contains total extracts from three plants (Melissa officinalis, Mentha spiccata and Coriandrum sativum).
Tong-xie-ning consists of dried substances of Paeonia lactiflora Pali, (root), Atractylodes macrocephala Koidz. (rhizome), Citrus reticulata Blanco, (unripe exocarp) and Allium macrostemon Bge. (bulb).
HKT is a composite of five crude herbs: Pinelliae Tuber, Hoelen, Magnoliae Cortex, Perillae Herba and Zingiberis Rhizoma.
Padma Lax is composed of Aloes, Calumba, Cascara, Myrobalan, Condurango, Elecampane, Frangula, Gentian, Pepper and Nux vomica.
RCT = randomised, controlled trial; QOL = quality of life.
Studies on curcumin (diferuoylmethane), an ingredient of turmeric (Curcuma longa) demonstrated improvement in healing of peptic ulcer and symptoms in non-ulcer dyspepsia but not in irritable bowel syndrome. Capsaicin, the active ingredient of another spice, red chilli pepper, has been evaluated in small RCTs, which yielded conflicting results in patients with functional dyspepsia. While one study reported significant improvement in overall symptoms, epigastric pain, fullness and nausea compared with placebo, an earlier placebo-controlled crossover trial was unable to show significant improvements in postprandial dyspepsia scores with capsaicin.
The combination of extracts of different plants appears to be advantageous to treat functional gastrointestinal disorders (FGIDs) compared with conventional chemically well-defined drugs. Nevertheless, several issues regarding herbal products deserve mention. Based on current evidence, the scientific validity of the use of many of these commercial natural products in FGIDs is severely limited, with quality control and regulatory issues continuing to be a concern. The available trials almost all suffer from significant methodological flaws making the results difficult to interpret. Although the short-term use appears relatively safe, the long-term safety of these agents has not been established. Further, because these natural products are not regulated as pharmaceuticals, questions regarding agent purity and potency could be raised.
Safety and efficacy issues
The quality of herb used and its chemical constitution is fundamental to understanding the product’s intended use and factors affecting its safety. It is the chemical constituents that are the basis for the pharmacological activity of a herbal product, and consequently for the therapeutic efficacy. Use of validated, reliable, and relevant methods for efficacy/toxicity studies with regulatory strategies are essential to create a stronger evidence base on the safety, efficacy and quality of the herbal products for functional gastrointestinal disorders.
Evaluation of herbal medicines: preclinical studies
Preclinical assays are essential to guarantee the safety and efficacy of natural products in functional gastrointestinal disorders (FGIDs). The pathophysiology of FGID is not firmly established, and is characterised by recurrent episodes of gastrointestinal symptoms with no structural alterations. Visceral hypersensitivity, disordered gastrointestinal motility and secretion are presently considered key mechanisms underlying FGID symptoms. Therefore, pharmacological studies with new herbal products for efficacy and safety assessment are carried out using in-vitro and in-vivo experimental models that helped define basic mechanisms of functional dyspepsia and IBS symptoms. Animal testing should follow the ethical considerations and the approval of the Institutional Committee on the Use of Animals for experimentation.
In-vitro and animal testing
The emerging therapies for functional gastrointestinal disorders are largely aimed at normalising pain perception and gastrointestinal motor and reflux function. Helicobacter pylori infection, NSAID consumption and severe physical stress are associated with FGID. For this reason, the most common pharmacological properties determined in the evaluation of drugs effective for FGID are the anti-Helicobacter, cytoprotection, visceral analgesic, spasmolytic, antisecretory, antidiarrheal and prokinetic effects. The requirement for each one of these studies include experimental animals (two species, one rodent and another non-rodent, 6-8 per group), appropriate controls (negative and positive), and product evaluation at three dose levels.
H. pylori may induce gastritis and chronic dyspepsia (functional non-ulcer dyspepsia or gastro-duodenal ulcer) in humans. Mongolian gerbils or BALB/c mice infected with H. pylori are often used as animal models to screen test compounds for their efficacy in reducing the extent of gastric ulceration or inflammation. Although these animals demonstrate gastric ulceration, virtually no gastritis is seen in the antrum of infected animals, but this is, however, the hallmark of human infection. The anti-H. pylori activity of a test drug can be assessed through in-vitro studies employing rat gastric epithelial cell cultures and H. pylori isolates from gastric mucosal biopsy patients. The minimum inhibitory concentration value of test drug is first established against H. pylori and then H. pylori is co-cultivated with rat gastric epithelial cells in the presence/absence of test drug at its minimum inhibitory concentration. A reduction in the activity of urease, a normal appearance of the epithelial cells on electron microscopic examination, a decrease in lipid peroxidation and lactate dehydrogenase suggests the possible anti-H. pylori activity of PS.
Gastric cytoprotection can be evaluated using rat/mouse/guinea pig models of gastric lesions induced by absolute ethanol, indometacin, histamine and immobilisation stress and, to elucidate the physiological mechanism, effects of herbal products on mucus secretion, acid secretion (pylorus-ligated animals), glutathione reserve, mucosal blood flow and gastric emptying time are analysed. In addition, to understand the pharmacological mechanism underlying the gastroprotection, the role of capsaicin-sensitive fibres, endogenous prostaglandins and nitric oxide may be verified, using capsaicin-desensitisation procedure, and/or analysis of prostaglandins by ELISA and nitrite/nitrate by Griess reaction or indirectly by the use of nitric oxide synthase inhibitors.
Visceral hyperalgesis is a characteristic feature of functional dyspepsia and irritable bowel syndrome. Visceral antihyperalgesic effects of herbals can be examined using animal models of nociception induced by intracolonic administration of mustard or capsaicin. These chemicals evoke both inflammatory and non-inflammatory pain through sensitisation of neurones at the peripheral and/or central sites, involving several neuropeptides and a great variety of inflammatory mediators. They serve as valuable tools in assessing gut pain and to study the possible mechanism.
Spasmolytic and antidiarrheal properties of test compounds can be assessed in well-established models such as the USSING-chamber, a pharmacological model for diarrhea, and the isolated guinea pig ileum, a model for modulatory effects on ileum contraction. The inhibitory effect observed in these models provides ex-vivo evidence for the spasmolytic and antidiarrheal activities of herbal products. Several studies have investigated abnormalities of serotonin signalling in IBS. Decreased postprandial serotonin plasma levels have been reported to occur in constipation-predominant IBS, and increased plasma levels have been reported to occur in diarrhea-predominant irritable bowel syndrome.
To verify the potential usefulness of herbals in diarrhea-prone IBS, in-vivo testing could be carried out in mice on castor oil- or croton oil-induced diarrhea, cholera toxin-induced intestinal secretion and on gastrointestinal transit induced by 5-HTP, using alosetron, an antagonist for 5-HT3 receptors and a known agent effective for diarrhea-predominant irritable bowel syndrome as a positive control. Further, morphine-induced gastrointestinal delay in mice may be used as a model to test the compound’s likely use in constipation-predominant IBS, using tegaserod, a 5-HT4 receptor agonist, as a positive control. Tegaserod is a known prokinetic agent that speeds small-bowel transit and right-colon transit in irritable bowel syndrome, reducing symptoms of constipation, pain and bloating.
Safety pharmacology
Clinical assessment of the gastrointestinal tract is often limited to measurements of transit time and observations of vomiting or diarrhea. In-vitro functional human tissue assays can be performed to measure a vast range of toxic effects of drugs under investigation, at the level of the organ, cell or even gene and these assays are considered an important adjunct to routine safety pharmacology tests. The cytotoxicity of new compounds can be determined by the MTT reduction assay using human lung fibroblasts (MRC-5). These models are rapid, less expensive and reveal mechanisms of action. The data obtained serve as signals of potential harmful effects in humans and are often superior to extrapolation from animals. The heart is a frequent site of toxicity of pharmaceutical compounds in humans, and, when developing a new drug, it is critical to conduct a thorough preclinical evaluation of its possible adverse effects on cardiac structure and function. Changes in cardiac morphology such as myocardial necrosis, hypertrophy or valvulopathy are assessed in laboratory animals. The potential proarrhythmic risk of new drugs is a major subject of concern and needs to be fully addressed before treatment of volunteers or patients takes place. The recommended tests to detect most arrythmic drugs were to determine the effects on cardiac ion channels, in particular I(Kr) potassium channel antagonism in vitro and prolongation of the QT interval, assessed in vivo, in telemetred dogs.
In-vivo animal safety data serve as important signal generators and in some cases, may stand alone as indicators of unreasonable risks. These include acute toxicity, and long-term toxicity, reproduction toxicity, genotoxicity and carcinogenicity studies. Knowledge of an ingredient’s pharmacokinetics and in-vivo metabolism will allow most appropriate interpretation of relevancy of the dose/concentration used in the in-vitro tests. Evidence of abnormalities from laboratory animal studies can be indicative of potential harm to humans.
Acute toxicity testing involves the study of toxic effects after a single (oral/parenteral) administration of the test compound with the objective to classify the substance associated on the basis of acute toxicity, identification of target involved in the acute toxic effect (signs: time of appearance, progression and reversibility), and to establish the dose intervals that may be of relevance to other toxicological studies. A long-term toxicity study (4-12 weeks) involves the repeated doses of the test substance, aimed to determine the maximum tolerable dose, the highest dose that does not result in toxic effects and the mechanism underlying the toxic effects in vivo by means of biochemical, behavioural and histopathological studies. Genotoxicity and carcinogenesis studies are important because several medicinal plants contain substances such as pyrrolizidine alkaloids, flavonoids, phorbol esters, etc., which can cause mutagenic effects. The Ames test using Salmonella typhimurium strains and the CHO (Chinese hamster ovary) chromosomal aberration test are the two most commonly used methods for the evaluation of genetic mutation and chromosome damage.
Evaluation of herbal medicines: controlled clinical trials
The choice of primary endpoint for a clinical trial is to demonstrate the efficacy of a therapeutic agent.
The Rome III Committee recommends two types of measures to assess the efficacy of new treatments for irritable bowel syndrome and functional dyspepsia:
• binary endpoints addressing the construct of relief (that is, adequate relief and satisfactory relief)
• an integrative symptom questionnaire that addresses the change in severity of a representative group of symptoms of irritable bowel syndrome (that is, the IBS Severity Scale).
The current evidence suggests that at present, adequate relief should be recognised by regulatory authorities as an acceptable primary endpoint in clinical trials. This analysis also suggests that data from individual clinical trials should be pooled and undergo meta-analysis, and that prospective studies should be considered to further characterise the performance of available endpoints as outcome measures in pharmacotherapeutic trials. Literature search reveals that few well-controlled, double-blind (placebo-controlled) trials have been carried out with herbal medicines (see Table: Clinical studies with herbal medicinals in gastrointestinal functional disorders). Meta-analyses of reviews published reveal several discrepancies, and these are mostly due to:
• lack of standardisation and quality control of the herbal drugs used in clinical trials
• use of different dosages of herbal medicines
• inadequate randomisation in most studies, and patients not properly selected
• numbers of patients in most trials insufficient for the attainment of statistical significance
• difficulties in establishing appropriate placebos because of the tastes, aromas, etc.
• wide variations in the duration of treatments using herbal medicines.
A few herbal products, e.g. STW 5 (Iberogast), Artichoke, Carmint, Tong-xie-ning (Chinese herbal formula), Hange-koboku-to (Kampoo medicine), and Padma Lax (Tibetan herbal medicine) have been evaluated in clinical trials, but they still have the difficulties mentioned above and need additional, well-controlled and appropriate randomised clinical trials to prove their efficacy.
To assess the efficacy of new herbals in functional gastrointestinal disorders, a double-blind, randomised, placebo-controlled, parallel group trial remains the preferred design. Investigators should include as broad a spectrum of patients as possible and should report recruitment strategies, inclusion/exclusion criteria, and attrition data. The primary analysis should be based on the proportion of patients in each treatment arm who satisfy a prespecified clinically meaningful change in a patient-reported symptom-improvement measure. Such measures of improvement are psychometrically validated subjective global assessments or a change from baseline in validated symptom guidelines and include an analysis of harms data and secondary outcome measures to support severity questionnaire. Data analysis should address all patients enrolled, using an intention-to-treat principle. Reporting of results should follow the Consolidated Standards for Reporting Trials or explain the primary outcome. Trials should be registered in a public location, prior to initiation, and should be reported even if the results are negative or inconclusive.
Conclusions
No standard therapy is currently available for functional gastrointestinal disorders such as functional dyspepsia and irritable bowel syndrome, which are characterised by multiple symptoms associated with disordered gut function. There is limited evidence for the efficacy, safety and tolerability of currently available conventional therapies and it may be that, with traditional herbal therapies, patients may respond better in symptom improvement because of their multicomponent nature with different active constituents having pleotropic actions. However, herbal medicinals should undergo the same procedures as conventional drugs and should not be considered differently because they are of natural origin. Preclinical studies on very many herbal extracts and their active constituents demonstrated interesting pharmacological properties relevant to functional dyspepsia and irritable bowel syndrome, but only few of them were taken to clinical trials with limited success. Future studies should address their effectiveness and safety in patients with FGIDs by the double-blind, randomised, placebo-controlled, parallel-group trial study design. The safety and their quality should be ensured through greater pharmacovigilance studies and by governmental regulatory mechanisms. To provide uniform quality of raw material, emphasis must be laid on domestication, production and biotechnological studies and genetic improvement of medicinal plants to provide uniform and high-quality raw material.