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Prokinetics and fundic relaxants in upper functional GI disorders
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Prokinetics and fundic relaxants in upper functional GI disorders Jan Tack Gastrointestinal prokinetics are a heterogeneous class of drugs that stimulate smooth muscle contractions to enhance gastric emptying and intestinal transit. Recently studied prokinetics include antidopaminergic agents (itopride), serotonergic agents (tegaserod and others), and motilin receptor agonists and ghrelin receptor agonists (mitemcinal, TZP101). It has been difficult to establish symptomatic benefit with prokinetic drugs in gastroparesis and functional dyspepsia, because of pathophysiological heterogeneity of the patient populations, a lack of well-accepted endpoints, and inconsistent relationships between changes in motor function and symptomatic outcome. Fundic relaxant drugs are a recent different approach to treatment of gastric motility disorders. Recently studied drugs include drugs under investigation including nitrates, serotonin reuptake blockers, 5-HT1A receptor agonists (buspirone and R137696), and muscarinc M1/M2 receptor antagonists (acotiamide or Z-338). Address Center for Gastroenterological Research, K.U. Leuven, Belgium Corresponding author: Tack, Jan ([email protected])
Current Opinion in Pharmacology 2008, 8:690–696 This review comes from a themed issue on Gastrointestinal Edited by Guy Boeckxstaens Available online 27th October 2008 1471-4892/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2008.09.009
Introduction Patients with putative gastric motor disorders constitute an important part of clinical gastroenterological practice. Normal gastric motor function includes gastric accommodation, which provides a reservoir during meal ingestion, gastric emptying at a rate that matches small bowel absorption, and interdigestive motility that eliminates indigestible particles. Disordered motility occurs when the processes of gastric emptying, reservoir function, or interdigestive motility are not properly controlled [1]. Absence of gastric phase III activity promotes gastric bezoar formation, and absence of intestinal phase III promotes bacterial overgrowth [2]. Impaired gastric accommodation may lead to defective reservoir function, inability to ingest normal-sized meals and weight loss [1,3]. Delayed gastric emptying leads to a gastroparesis syndrome with prolonged stasis and fermentation of food Current Opinion in Pharmacology 2008, 8:690–696
[4]. Abnormally rapid gastric emptying causes duodenal caloric overload and dumping syndrome [5]. Functional dyspepsia (FD) and gastroparesis are the main clinical syndromes that have been associated to gastric motor dysfunction. FD is characterized by symptoms of postprandial fullness, early satiation, epigastric pain, and burning, in the absence of a readily identifiable organic cause [6]. Gastroparesis is diagnosed in case of severely delayed gastric emptying in the absence of mechanical obstruction, and can be caused by a variety of gastrointestinal and systemic causes [4]. However, delayed gastric emptying is found in up to 30% of FD patients [7], and the distinction between FD with delayed emptying and idiopathic gastroparesis has not been clearly defined. Recent studies have reported the occurrence of impaired gastric accommodation in FD and a number of other clinical dysmotility syndromes, and it has been suggested that this may contribute to symptom generation [8]. Dumping syndrome, which mainly occurs after partial or complete gastrectomy, or vagotomy, is characterized by rapid gastric emptying accompanied by vasomotor and gastrointestinal symptoms. Rapid gastric emptying was also reported in a subset of FD patients, but it is unclear whether this contributes to symptom generation through a dumping-related mechanism [9]. Pharmacological approaches to correct abnormal gastric motility are considered a valid therapeutic approach in FD and gastroparesis. Gastrointestinal prokinetics are drugs that stimulate gastric smooth muscle contractions, leading to enhanced gastric emptying. Prokinetics have long been considered the drugs of choice for the treatment of upper gastrointestinal functional and motor disorders, on the basis of the assumption that delayed gastric emptying or poorly coordinated antro-pyloro-duodenal coordination was present in the vast majority of these patients. Problems with this concept are the poor correlation between delayed emptying and symptoms and the frequent co-existence of other sensorimotor disorders that may also contribute to symptom generation [7,10]. Impaired gastric accommodation and visceral hypersensitivity, using fundic relaxants or visceral analgesics, are other attractive targets for drug development in sensorimotor disorders of the upper gastrointestinal tract.
Prokinetic drugs 5-HT4 receptor agonists
Gastroprokinetics are a heterogenous class of compounds acting through different types of receptors. The efficacy of available prokinetics in FD has been controversial [11,12]. A meta-analysis, mainly based on studies with www.sciencedirect.com
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cisapride, suggested superiority of prokinetics to placebo in FD, but concerns were raised about publication bias, and cisapride has been withdrawn for safety concerns [11]. Other prokinetic agents, like the motilin receptor agonist, ABT-229, have been unsuccessful in the treatment of FD [13]. The pharmacology and efficacy of prokinetic drugs has recently been reviewed [12]. This review focuses on recent drug development for FD and gastroparesis. Tegaserod
Cisapride, the first prokinetic extensively used in FD and gastroparesis, is a non-selective 5-HT4 receptor agonist with partial weak 5-HT3 antagonist effect [11,12]. The drug has been withdrawn owing to the occurrence of cardiac arrhythmias. These effects were considered unrelated to the 5-HT4 agonism, but were to be due to cisapride’s benzamide structure, which blocks cardiac human ether-a`-go-go-related gene (HERG) potassium channels and prolongs the QT interval [14]. Tegaserod, an aminoguanidine indole compound, is a partial 5-HT4 receptor agaonist that can also block 5HT2b receptors [14,15]. The drug has mainly been evaluated for constipation and constipation-predominant irritable bowel syndrome (IBS) [16,17]. Tegaserod accelerates gastric emptying and enhances gastric accommodation in healthy volunteers [18,19]. Tegaserod is able to normalize delayed gastric emptying, enhance gastric accommodation, and improve impaired antroduodenal motility in FD and gastroparesis [20,21,22]. An extensive phase 2 study program in FD evaluated the efficacy of several doses of tegaserod in patients with normal or delayed gastric emptying [23,24]. These studies suggested that tegaserod 6 mg b.i.d. can improve dysmotility-like FD symptoms in women, besides showing dose-dependent enhancement of gastric emptying in FD with delayed emptying [23,24]. Tegaserod 6 mg b.i.d. was further evaluated in two phase 3 randomized controlled trials in women with dysmotilitylike FD. The two primary endpoints were the percentage of days with satisfactory symptom relief and the symptom severity on a composite average daily severity score. Statistical significance for both endpoints was obtained in one study, but not in the other, and overall therapeutic gain seemed small, although it was larger in the patients with higher baseline symptom severity [25]. The drug was well tolerated in this FD program, but was meanwhile withdrawn for increased incidence of cardiovascular ischemic events. Other 5-HT4 receptor agonists
Renzapride is a substituted benzamide with both 5-HT4 receptor agonist and 5-HT3 receptor antagonist properties, which was mainly investigated in constipation-prewww.sciencedirect.com
dominant IBS [26,27]. Renzapride accelerates gastric emptying in healthy volunteers and in diabetic gastroparesis, suggesting a potential for application in upper gastrointestinal disorders [28,29]. Electrocardiographic and in vitro studies of the HERG channel showed no QT prolongating effects [30]. Mosapride is another benzamide derivative that exhibits both 5-HT4 receptor agonist and 5-HT3 receptor antagonist properties and is commercially available in several Asian countries [12,14]. Mosapride had no significant effect on the HERG channel in vitro [31]. Mosapride has been evaluated for the treatment of FD and gastroparesis, as it was shown to have gastroprokinetic effects in healthy volunteers [32]. However, a European study in FD showed no benefit of mosapride over placebo [33]. Prucalopride belongs to a new class of drugs known as benzofurancarboxamides and is a highly selective 5-HT4 receptor agonist [14]. Prucalopride enhances transit through the stomach, small bowel, and colon in constipated patients [34]. The drug has been extensively evaluated in clinical trials in chronic constipation [35]. ATI-7505 is derived from cisapride, with modifications aimed at elimination of the HERG channel and cytochrome p450 affinities. A healthy volunteer’s study confirmed the prokinetic properties of the drug, which is now evaluated in clinical trials in chronic constipation and FD [36]. TD-5108 is another selective 5HT4 receptor agonist, currently evaluated for the treatment of chronic constipation [37]. Dopamine2 receptor antagonists
The rationale for using antidopaminergic agents was based on the presence of D2 receptors in the gastrointestinal wall of several mammals, inhibiting motility. Blockade of these inhibitory receptors by selective antagonists, such as domperidone and metoclopramide, has prokinetic effects [11,12]. In addition, D2antagonists also suppress nausea and vomiting in the area postrema. Levosulpiride, clebopride, alizapride, and bromopride are other antidopaminergic prokinetics and anti-emetics, which are available in some selected countries only [11,12]. Itopride
Itopride is a dopamine D2 antagonist and acetylcholinesterase inhibitor that was intensively studied in FD. In a dog model of gastric hypomotility, itopride dose-dependently restored motor activity [38]. Itopride is marketed in several Asian countries for ‘gastritis’. A phase IIb placebo-controlled trial found significantly more responders to itopride, on the basis of a global efficacy measure [39]. The co-primary outcome measures were the change in total score on the Leeds Dyspepsia Questionnaire (LDQ) and the responder rate based on the pain and fullness subscores. However, no significant improvement over placebo in reduction of FD symptoms was observed in two subsequent Phase III trials [40]. The phase III outcome measures were similar to phase II, but in contrast Current Opinion in Pharmacology 2008, 8:690–696
692 Gastrointestinal
to phase II, phase III excluded the presence of heartburn as a symptom. Mechanistic studies in healthy controls and diabetic patients showed no significant effects of itopride on gastric emptying rates [41,42].
Motilin and ghrelin receptor agonists
Erythromycin, a macrolide antibiotic, was the first nonpeptide compound for which agonism at the motilin receptor and strong gastroprokinetic properties were demonstrated [11,12]. Since then, several motilin receptor agonists without antibiotic properties, called motilides, have been evaluated for the treatment of gastroparesis and FD. So far, none of these compounds showed beneficial effects over placebo [11–13]. As motilin was shown to inhibit gastric accommodation and to induce early satiation, it has been proposed that this component of the motilide-induced motor activity caused symptoms that negatively affected potential benefits from enhanced gastric emptying [43,44]. It is conceivable that lower dose ranges enhance gastric emptying without affecting gastric accommodation, and a number of compounds are still under evaluation. GM 611 (mitemcinal) is an erythromycin derivative with motilin receptor agonistic and gastroprokinetic properties [45]. In a controlled study in diabetic gastroparesis, overall efficacy was similar to placebo, but post hoc analysis suggested a better response in patients with lower body mass index and with lower hemoglobin A1 [46]. More-
over, symptomatic response seemed higher in normal compared to delayed gastric emptying [46]. Ghrelin is a 28-amino acid motilin-related peptide that is the natural ligand for the growth-hormone secretagogue receptor (GHSR), but also has distinct effects on gastrointestinal motility [47,48]. Ghrelin has a strong stimulatory effect on gastric interdigestive motility in man and enhances gastric emptying in health and in gastroparesis [49,50,51,52]. In idiopathic gastroparesis, ghrelin enhanced gastric emptying and also improved mealinduced symptoms, in spite of an inhibitory effect on gastric accommodation [52,53]. Non-peptide ghrelin agonists are currently under evaluation in gastroparesis and postoperative ileus [54]. Other prokinetic drugs
Botulinum toxin binds to the synaptosomal-associatedprotein-25 to block acetylcholine release from excitatory nerve endings. Uncontrolled studies suggest benefit from intra-pyloric injection of botulinum toxin in gastroparesis, but two controlled studies showed no benefit over saline [55,56,57,58].
Fundic relaxant drugs Owing to the central role of NO, NO donors have been used to enhance gastric relaxation and to reduce dyspeptic symptoms [7,8,59]. However, the effect of nitrates was short-lasting and associated with major side effects like hypotension and headache. Sildenafil is an inhibitor of
Figure 1
Targets for recently studied prokinetic and fundic relaxant drugs on enteric neurons and muscle cells in the stomach. Current Opinion in Pharmacology 2008, 8:690–696
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phosphodiesterase-5, causing smooth muscle cell relaxation through a prolongation of the effect of NO. In a controlled study in healthy volunteers, sildenafil significantly enhanced accommodation, but studies in FD patients are lacking [60]. As 5-HT receptors are involved in the accommodation reflex [7] the use of several serotonergic agents has been explored. Short-term pretreatment with paroxetine, a
selective serotonin reuptake inhibitor (SSRI), enhanced gastric accommodation to a meal in healthy volunteers [61] but has not been formally evaluated in FD. In line with animal studies suggesting involvement of a 5-HT1like receptor, sumatriptan, a 5-HT1B/1D receptor agonist used in migraine, was shown to relax the stomach in healthy subjects [62,63]. In acute studies, similar effects were obtained in FD patients with impaired accommodation, where this was associated with decreased meal-
Table 1 Overview of recently studied prokinetic and fundic relaxant drugs, their pharmacological profile, pharmacodynamic properties and results of clinical trials. Drug class Prokinetic drugs 5-HT4 receptor agonists
Drug name Tegaserod
Renzapride
Mosapride
Gastric motor effects
Clinical trial results in gastric motor disorders
Accelerates gastric emptying in health and in gastroparesis Enhances gastric accommodation in health and in FD Enhances gastric emptying in health and in diabetic gastroparesis Enhances gastric emptying in health
Phase 2 in FD: no benefit over placebo; post hoc potential efficacy in females Phase 3 in FD: Mixed results
Phase 2 in FD significant benefit
/
Phase 2 in FD: no benefit over placebo
Dopamine2 receptor antagonists
Itopride
Decreases gastric accommodation in health
Motilin receptor agonists Ghrelin receptor agonists
Mitemcinal
Phase 2 in diabetic gastroparesis: no benefit over placebo; post hoc potential benefit in subgroups /
Synaptosomalassociated protein-25 blockers
Botulinum toxin
Enhances gastric emptying in gastroparesis Enhances gastric emptying in animals; enhances motility in a model of postoperative ileus Enhances gastric emptying in uncontrolled studies
Nitroglycerine
Enhances gastric accommodation in health and in FD
/
Phosphodiesterase inhibitors
Sildenafil
Enhances gastric accommodation in health Delays gastric emptying in health
/
Selective serotonin reuptake inhibitors
Paroxetine
Enhances gastric accommodation in health
/
5-HT1B/D receptor agonists
Sumatriptan
Enhances gastric accommodation in health and in FD Delays gastric emptying in health
/
5-HT3 receptor agonists
MKC-733
Enhances gastric accommodation in health Delays gastric emptying in health
/
Alpha 2 adrenergic agonists
Clonidine
Enhances gastric accommodation in health
/
5-HT1A receptor agonists
Buspirone
Relaxes the proximal stomach in health Delays gastric emptying in health Relaxes the proximal stomach in health
Potential benefit in a small pilot study
May enhance accommodation in FD
Phase 2a in FD: potential benefit Phase 2 in FD: significant benefit
Phase 3 in FD no benefit over placebo
Fundus-relaxing drugs Nitrates
TZP-101
R137696 M1/M2 muscarinic receptor blockers
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Acotiamide (Z338, YM443)
Controlled studies: no benefit over placebo
Phase 2 in FD: no benefit over placebo
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induced satiety [3]. However, intranasal administration of the drug failed to induce a significant relaxation in healthy volunteers, probably owing to lower bio-availability [64]. As mentioned above, 5-HT4 receptor agonists may enhance gastric accommodation through the activation of presynaptic receptors [12,19,22]. Furthermore, the 5HT3 agonist MKC-733 induced gastric relaxation in healthy volunteers, but this may have occurred as a consequence of nausea [65].
targets and optimized trial design for the treatment of this common clinical problem (Figure 1, Table 1).
An alternative way to promote gastric accommodation is inhibition of excitatory motor neurons, which are mainly cholinergic. This can be achieved through activation of presynaptic inhibitory a2 receptors or 5-HT1A receptors, or through inhibition of presynaptic muscarinic receptors [7]. Buspirone, a 5-HT1A receptor agonist with anxiolytic properties dose-dependently enhances gastric accommodation and delays gastric emptying in man [66]. R-137696, a newly developed 5-HT1A receptor agonist, also dosedependently relaxes the proximal stomach in man [67]. A placebo-controlled multi-center study failed to show any symptomatic benefit during a four-week treatment with R-137696 in FD, possibly owing to desensitization [68]. Presynaptic a2-receptors are present on intrinsic cholinergic nerve endings in the stomach, and acute administration of the a2-agonist clonidine enhanced gastric accommodation [69]. To date, no clinical studies with clonidine in FD are available.
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Conclusion Currently available agents for treatment of gastric motility disorders include several different classes of agents. Abilities to enhance gastric emptying or to enhance gastric accommodation have been identified as putatively relevant underlying pharmacodynamic mechanisms. Effective drug development for gastric motor disorders is hampered by pathophysiological heterogeneity of the patient population, by a lack of well-accepted endpoints, and by an inconsistent relationship between changes in motor function and symptomatic outcome. Nevertheless, a number of phase 2 trials have shown symptomatic benefit with selected agents. Experience from these studies is likely to lead to better identification of relevant Current Opinion in Pharmacology 2008, 8:690–696
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63. Tack J, Coulie B, Wilmer A, Andrioli A, Janssens J: Influence of sumatriptan on gastric fundus tone and on the perception of gastric distension in man. Gut 2000, 46:468-473.
51. Tack J, Depoortere I, Bisschops R, Verbeke K, Janssens J, Peeters T: Influence of ghrelin on gastric emptying and mealrelated symptoms in idiopathic gastroparesis. Aliment Pharmacol Ther 2005, 22:847-853. First paper to establish therapeutic potential for ghrelin in gastroparesis. 52. Murray CD, Martin NM, Patterson M, Taylor SA, Ghatei MA, Kamm MA, Johnston C, Bloom SR, Emmanuel AV: Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study. Gut 2005, 54:1693-1698. 53. Ang D, Nicolai H, Vos R, Mimidis K, Akyuz F, Vanden Berghe P, Sifrim D, Depoortere I, Peeters T, Tack J: Influence of ghrelin on the gastric accommodation reflex and on meal-induced satiety in man. Neurogastroenterol Motil 2008, in press. 54. Lasseter KC, Shaughnessy L, Cummings D, Pezzullo JC, Wargin W, Gagnon R, Oliva J, Kosutic G: Ghrelin agonist (TZP-101): safety, pharmacokinetics and pharmacodynamic evaluation in healthy volunteers: a phase I, first-in-human study. J Clin Pharmacol 2008, 48:193-202. 55. Miller LS, Szych GA, Kantor SB, Bromer MQ, Knight LC, Maurer AH, Fisher RS, Parkman HP: Treatment of idiopathic gastroparesis with injection of botulinum toxin into the pyloric sphincter muscle. Am J Gastroenterol 2002, 97:1653-1660. 56. Arts J, van Gool S, Caenepeel P, Verbeke K, Janssens J, Tack J: Influence of intrapyloric botulinum toxin injection on gastric emptying and meal-related symptoms in gastroparesis patients. Aliment Pharmacol Ther 2006, 24:661-667. 57. Arts J, Holvoet L, Caenepeel P, Bisschops R, Sifrim D, Verbeke K, Janssens J, Tack J: Clinical trial: a randomized-controlled crossover study of intrapyloric injection of botulinum toxin in gastroparesis. Aliment Pharmacol Ther 2007, 26:1251-1258. This paper, as well as the next one, confirms again the unreliability of uncontrolled trials in motility disorders such as gastroparesis. 58. Friedenberg FK, Palit A, Parkman HP, Hanlon A, Nelson DB: Botulinum toxin A for the treatment of delayed gastric emptying. Am J Gastroenterol 2008, 103:416-423. This paper, as well as the previous one, confirms again the unreliability of uncontrolled trials in motility disorders such as gastroparesis. 59. Gilja OH, Hausken T, Bang CJ, Berstad A: Effect of glyceryl trinitrate on gastric accommodation and symptoms in functional dyspepsia. Dig Dis Sci 1997, 42:2124-2131. 60. Sarnelli G, Sifrim D, Janssens J, Tack J: Influence of sildenafil on gastric sensorimotor function in humans. Am J Physiol Gastrointest Liver Physiol 2004, 287:G988-G992.
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64. Sarnelli G, Janssens J, Tack J: Effect of intranasal sumatriptan on gastric tone and sensitivity to distension. Dig Dis Sci 2001, 46:1591-1595. 65. Coleman NS, Marciani L, Blackshaw E, Wright J, Parker M, Yano T, Yamazaki S, Chan PQ, Wilde K, Gowland PA et al.: Effect of a novel 5-HT3 receptor agonist MKC-733 on upper gastrointestinal motility in humans. Aliment Pharmacol Ther 2003, 18:1039-1048. 66. Van Oudenhove L, Kindt S, Vos R, Coulie B, Tack J: Influence of buspirone on gastric sensorimotor function in man. Aliment Pharmacol Ther 2008. [Epub ahead of print]. 67. Boeckxstaens GE, Tytgat GN, Wajs E, van Nueten L, de Ridder F, Meulemans A, Tack J: The influence of the novel 5-HT1A agonist R137696 on the proximal stomach function in healthy volunteers. Neurogastroenterol Motil 2006, 18:919-926. Proof-of-concept study of the relaxatory effect of 5-HT1A receptor stimulation on the proximal stomach in man. 68. Tack J, Van Elzen B, Tytgat G, Wajs E, Van Nueten L, De Ridder F, Boeckxstaens G: A placebo-controlled trial of the 5-HT1A agonist R-137696 on symptoms, visceral hypersensitivity and on impaired accommodation in functional dyspepsia. Neurogastroenterol Motil 2008, submitted for publication. 69. Thumshirn M, Camilleri M, Choi MG, Zinsmeister AR: Modulation of gastric sensory and motor functions by nitrergic and alpha2-adrenergic agents in humans. Gastroenterology 1999, 116:573-585. 70. Doi Y, Murasaki O, Kaibara M, Uezono Y, Hayashi H, Yano K, Taniyama K: Characterization of functional effect of Z-338, a novel gastroprokinetic agent, on the muscarinic M1, M2, and M3 receptors expressed in Xenopus oocytes. Eur J Pharmacol 2004, 505:31-35. 71. Tack J, Masclee A, Heading RC, Berstad A, Piessevaux H, Popiela T, Vandenberghe A, Kato H: A dose-ranging, placebo-controlled pilot trial of acotiamide in patients with functional dyspepsia. Neurogastroenterol Motil 2008, in press. 72. Seto K, Sasaki T, Katsunuma K, Kobayashi N, Tanaka K, Tack J: Z338, a novel gastroprokinetic agent, restores delayed gastric emptying and feeding inhibition induced by restraint stress in rats. Neurogastroenterol Motil 2008, 20:1051-1059 Epub ahead of print. 73. Talley NJ, Tack J, Kowalski D, Borton MA, Barve A: A novel acetylcholine esterase inhibitor acotiamide hydrochloride (ym443) in functional dyspepsia: efficacy in a randomized, double-blind, placebo-controlled dose ranging trial. Gastroenterology 2008, 4(Suppl 1):A-157 (abstract).
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Prokinetics and fundic relaxants in upper functional GI disorders Jan Tack Gastrointestinal prokinetics are a heterogeneous class of drugs that stimulate smooth muscle contractions to enhance gastric emptying and intestinal transit. Recently studied prokinetics include antidopaminergic agents (itopride), serotonergic agents (tegaserod and others), and motilin receptor agonists and ghrelin receptor agonists (mitemcinal, TZP101). It has been difficult to establish symptomatic benefit with prokinetic drugs in gastroparesis and functional dyspepsia, because of pathophysiological heterogeneity of the patient populations, a lack of well-accepted endpoints, and inconsistent relationships between changes in motor function and symptomatic outcome. Fundic relaxant drugs are a recent different approach to treatment of gastric motility disorders. Recently studied drugs include drugs under investigation including nitrates, serotonin reuptake blockers, 5-HT1A receptor agonists (buspirone and R137696), and muscarinc M1/M2 receptor antagonists (acotiamide or Z-338). Address Center for Gastroenterological Research, K.U. Leuven, Belgium Corresponding author: Tack, Jan ([email protected])
Current Opinion in Pharmacology 2008, 8:690–696 This review comes from a themed issue on Gastrointestinal Edited by Guy Boeckxstaens Available online 27th October 2008 1471-4892/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2008.09.009
Introduction Patients with putative gastric motor disorders constitute an important part of clinical gastroenterological practice. Normal gastric motor function includes gastric accommodation, which provides a reservoir during meal ingestion, gastric emptying at a rate that matches small bowel absorption, and interdigestive motility that eliminates indigestible particles. Disordered motility occurs when the processes of gastric emptying, reservoir function, or interdigestive motility are not properly controlled [1]. Absence of gastric phase III activity promotes gastric bezoar formation, and absence of intestinal phase III promotes bacterial overgrowth [2]. Impaired gastric accommodation may lead to defective reservoir function, inability to ingest normal-sized meals and weight loss [1,3]. Delayed gastric emptying leads to a gastroparesis syndrome with prolonged stasis and fermentation of food Current Opinion in Pharmacology 2008, 8:690–696
[4]. Abnormally rapid gastric emptying causes duodenal caloric overload and dumping syndrome [5]. Functional dyspepsia (FD) and gastroparesis are the main clinical syndromes that have been associated to gastric motor dysfunction. FD is characterized by symptoms of postprandial fullness, early satiation, epigastric pain, and burning, in the absence of a readily identifiable organic cause [6]. Gastroparesis is diagnosed in case of severely delayed gastric emptying in the absence of mechanical obstruction, and can be caused by a variety of gastrointestinal and systemic causes [4]. However, delayed gastric emptying is found in up to 30% of FD patients [7], and the distinction between FD with delayed emptying and idiopathic gastroparesis has not been clearly defined. Recent studies have reported the occurrence of impaired gastric accommodation in FD and a number of other clinical dysmotility syndromes, and it has been suggested that this may contribute to symptom generation [8]. Dumping syndrome, which mainly occurs after partial or complete gastrectomy, or vagotomy, is characterized by rapid gastric emptying accompanied by vasomotor and gastrointestinal symptoms. Rapid gastric emptying was also reported in a subset of FD patients, but it is unclear whether this contributes to symptom generation through a dumping-related mechanism [9]. Pharmacological approaches to correct abnormal gastric motility are considered a valid therapeutic approach in FD and gastroparesis. Gastrointestinal prokinetics are drugs that stimulate gastric smooth muscle contractions, leading to enhanced gastric emptying. Prokinetics have long been considered the drugs of choice for the treatment of upper gastrointestinal functional and motor disorders, on the basis of the assumption that delayed gastric emptying or poorly coordinated antro-pyloro-duodenal coordination was present in the vast majority of these patients. Problems with this concept are the poor correlation between delayed emptying and symptoms and the frequent co-existence of other sensorimotor disorders that may also contribute to symptom generation [7,10]. Impaired gastric accommodation and visceral hypersensitivity, using fundic relaxants or visceral analgesics, are other attractive targets for drug development in sensorimotor disorders of the upper gastrointestinal tract.
Prokinetic drugs 5-HT4 receptor agonists
Gastroprokinetics are a heterogenous class of compounds acting through different types of receptors. The efficacy of available prokinetics in FD has been controversial [11,12]. A meta-analysis, mainly based on studies with www.sciencedirect.com
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cisapride, suggested superiority of prokinetics to placebo in FD, but concerns were raised about publication bias, and cisapride has been withdrawn for safety concerns [11]. Other prokinetic agents, like the motilin receptor agonist, ABT-229, have been unsuccessful in the treatment of FD [13]. The pharmacology and efficacy of prokinetic drugs has recently been reviewed [12]. This review focuses on recent drug development for FD and gastroparesis. Tegaserod
Cisapride, the first prokinetic extensively used in FD and gastroparesis, is a non-selective 5-HT4 receptor agonist with partial weak 5-HT3 antagonist effect [11,12]. The drug has been withdrawn owing to the occurrence of cardiac arrhythmias. These effects were considered unrelated to the 5-HT4 agonism, but were to be due to cisapride’s benzamide structure, which blocks cardiac human ether-a`-go-go-related gene (HERG) potassium channels and prolongs the QT interval [14]. Tegaserod, an aminoguanidine indole compound, is a partial 5-HT4 receptor agaonist that can also block 5HT2b receptors [14,15]. The drug has mainly been evaluated for constipation and constipation-predominant irritable bowel syndrome (IBS) [16,17]. Tegaserod accelerates gastric emptying and enhances gastric accommodation in healthy volunteers [18,19]. Tegaserod is able to normalize delayed gastric emptying, enhance gastric accommodation, and improve impaired antroduodenal motility in FD and gastroparesis [20,21,22]. An extensive phase 2 study program in FD evaluated the efficacy of several doses of tegaserod in patients with normal or delayed gastric emptying [23,24]. These studies suggested that tegaserod 6 mg b.i.d. can improve dysmotility-like FD symptoms in women, besides showing dose-dependent enhancement of gastric emptying in FD with delayed emptying [23,24]. Tegaserod 6 mg b.i.d. was further evaluated in two phase 3 randomized controlled trials in women with dysmotilitylike FD. The two primary endpoints were the percentage of days with satisfactory symptom relief and the symptom severity on a composite average daily severity score. Statistical significance for both endpoints was obtained in one study, but not in the other, and overall therapeutic gain seemed small, although it was larger in the patients with higher baseline symptom severity [25]. The drug was well tolerated in this FD program, but was meanwhile withdrawn for increased incidence of cardiovascular ischemic events. Other 5-HT4 receptor agonists
Renzapride is a substituted benzamide with both 5-HT4 receptor agonist and 5-HT3 receptor antagonist properties, which was mainly investigated in constipation-prewww.sciencedirect.com
dominant IBS [26,27]. Renzapride accelerates gastric emptying in healthy volunteers and in diabetic gastroparesis, suggesting a potential for application in upper gastrointestinal disorders [28,29]. Electrocardiographic and in vitro studies of the HERG channel showed no QT prolongating effects [30]. Mosapride is another benzamide derivative that exhibits both 5-HT4 receptor agonist and 5-HT3 receptor antagonist properties and is commercially available in several Asian countries [12,14]. Mosapride had no significant effect on the HERG channel in vitro [31]. Mosapride has been evaluated for the treatment of FD and gastroparesis, as it was shown to have gastroprokinetic effects in healthy volunteers [32]. However, a European study in FD showed no benefit of mosapride over placebo [33]. Prucalopride belongs to a new class of drugs known as benzofurancarboxamides and is a highly selective 5-HT4 receptor agonist [14]. Prucalopride enhances transit through the stomach, small bowel, and colon in constipated patients [34]. The drug has been extensively evaluated in clinical trials in chronic constipation [35]. ATI-7505 is derived from cisapride, with modifications aimed at elimination of the HERG channel and cytochrome p450 affinities. A healthy volunteer’s study confirmed the prokinetic properties of the drug, which is now evaluated in clinical trials in chronic constipation and FD [36]. TD-5108 is another selective 5HT4 receptor agonist, currently evaluated for the treatment of chronic constipation [37]. Dopamine2 receptor antagonists
The rationale for using antidopaminergic agents was based on the presence of D2 receptors in the gastrointestinal wall of several mammals, inhibiting motility. Blockade of these inhibitory receptors by selective antagonists, such as domperidone and metoclopramide, has prokinetic effects [11,12]. In addition, D2antagonists also suppress nausea and vomiting in the area postrema. Levosulpiride, clebopride, alizapride, and bromopride are other antidopaminergic prokinetics and anti-emetics, which are available in some selected countries only [11,12]. Itopride
Itopride is a dopamine D2 antagonist and acetylcholinesterase inhibitor that was intensively studied in FD. In a dog model of gastric hypomotility, itopride dose-dependently restored motor activity [38]. Itopride is marketed in several Asian countries for ‘gastritis’. A phase IIb placebo-controlled trial found significantly more responders to itopride, on the basis of a global efficacy measure [39]. The co-primary outcome measures were the change in total score on the Leeds Dyspepsia Questionnaire (LDQ) and the responder rate based on the pain and fullness subscores. However, no significant improvement over placebo in reduction of FD symptoms was observed in two subsequent Phase III trials [40]. The phase III outcome measures were similar to phase II, but in contrast Current Opinion in Pharmacology 2008, 8:690–696
692 Gastrointestinal
to phase II, phase III excluded the presence of heartburn as a symptom. Mechanistic studies in healthy controls and diabetic patients showed no significant effects of itopride on gastric emptying rates [41,42].
Motilin and ghrelin receptor agonists
Erythromycin, a macrolide antibiotic, was the first nonpeptide compound for which agonism at the motilin receptor and strong gastroprokinetic properties were demonstrated [11,12]. Since then, several motilin receptor agonists without antibiotic properties, called motilides, have been evaluated for the treatment of gastroparesis and FD. So far, none of these compounds showed beneficial effects over placebo [11–13]. As motilin was shown to inhibit gastric accommodation and to induce early satiation, it has been proposed that this component of the motilide-induced motor activity caused symptoms that negatively affected potential benefits from enhanced gastric emptying [43,44]. It is conceivable that lower dose ranges enhance gastric emptying without affecting gastric accommodation, and a number of compounds are still under evaluation. GM 611 (mitemcinal) is an erythromycin derivative with motilin receptor agonistic and gastroprokinetic properties [45]. In a controlled study in diabetic gastroparesis, overall efficacy was similar to placebo, but post hoc analysis suggested a better response in patients with lower body mass index and with lower hemoglobin A1 [46]. More-
over, symptomatic response seemed higher in normal compared to delayed gastric emptying [46]. Ghrelin is a 28-amino acid motilin-related peptide that is the natural ligand for the growth-hormone secretagogue receptor (GHSR), but also has distinct effects on gastrointestinal motility [47,48]. Ghrelin has a strong stimulatory effect on gastric interdigestive motility in man and enhances gastric emptying in health and in gastroparesis [49,50,51,52]. In idiopathic gastroparesis, ghrelin enhanced gastric emptying and also improved mealinduced symptoms, in spite of an inhibitory effect on gastric accommodation [52,53]. Non-peptide ghrelin agonists are currently under evaluation in gastroparesis and postoperative ileus [54]. Other prokinetic drugs
Botulinum toxin binds to the synaptosomal-associatedprotein-25 to block acetylcholine release from excitatory nerve endings. Uncontrolled studies suggest benefit from intra-pyloric injection of botulinum toxin in gastroparesis, but two controlled studies showed no benefit over saline [55,56,57,58].
Fundic relaxant drugs Owing to the central role of NO, NO donors have been used to enhance gastric relaxation and to reduce dyspeptic symptoms [7,8,59]. However, the effect of nitrates was short-lasting and associated with major side effects like hypotension and headache. Sildenafil is an inhibitor of
Figure 1
Targets for recently studied prokinetic and fundic relaxant drugs on enteric neurons and muscle cells in the stomach. Current Opinion in Pharmacology 2008, 8:690–696
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phosphodiesterase-5, causing smooth muscle cell relaxation through a prolongation of the effect of NO. In a controlled study in healthy volunteers, sildenafil significantly enhanced accommodation, but studies in FD patients are lacking [60]. As 5-HT receptors are involved in the accommodation reflex [7] the use of several serotonergic agents has been explored. Short-term pretreatment with paroxetine, a
selective serotonin reuptake inhibitor (SSRI), enhanced gastric accommodation to a meal in healthy volunteers [61] but has not been formally evaluated in FD. In line with animal studies suggesting involvement of a 5-HT1like receptor, sumatriptan, a 5-HT1B/1D receptor agonist used in migraine, was shown to relax the stomach in healthy subjects [62,63]. In acute studies, similar effects were obtained in FD patients with impaired accommodation, where this was associated with decreased meal-
Table 1 Overview of recently studied prokinetic and fundic relaxant drugs, their pharmacological profile, pharmacodynamic properties and results of clinical trials. Drug class Prokinetic drugs 5-HT4 receptor agonists
Drug name Tegaserod
Renzapride
Mosapride
Gastric motor effects
Clinical trial results in gastric motor disorders
Accelerates gastric emptying in health and in gastroparesis Enhances gastric accommodation in health and in FD Enhances gastric emptying in health and in diabetic gastroparesis Enhances gastric emptying in health
Phase 2 in FD: no benefit over placebo; post hoc potential efficacy in females Phase 3 in FD: Mixed results
Phase 2 in FD significant benefit
/
Phase 2 in FD: no benefit over placebo
Dopamine2 receptor antagonists
Itopride
Decreases gastric accommodation in health
Motilin receptor agonists Ghrelin receptor agonists
Mitemcinal
Phase 2 in diabetic gastroparesis: no benefit over placebo; post hoc potential benefit in subgroups /
Synaptosomalassociated protein-25 blockers
Botulinum toxin
Enhances gastric emptying in gastroparesis Enhances gastric emptying in animals; enhances motility in a model of postoperative ileus Enhances gastric emptying in uncontrolled studies
Nitroglycerine
Enhances gastric accommodation in health and in FD
/
Phosphodiesterase inhibitors
Sildenafil
Enhances gastric accommodation in health Delays gastric emptying in health
/
Selective serotonin reuptake inhibitors
Paroxetine
Enhances gastric accommodation in health
/
5-HT1B/D receptor agonists
Sumatriptan
Enhances gastric accommodation in health and in FD Delays gastric emptying in health
/
5-HT3 receptor agonists
MKC-733
Enhances gastric accommodation in health Delays gastric emptying in health
/
Alpha 2 adrenergic agonists
Clonidine
Enhances gastric accommodation in health
/
5-HT1A receptor agonists
Buspirone
Relaxes the proximal stomach in health Delays gastric emptying in health Relaxes the proximal stomach in health
Potential benefit in a small pilot study
May enhance accommodation in FD
Phase 2a in FD: potential benefit Phase 2 in FD: significant benefit
Phase 3 in FD no benefit over placebo
Fundus-relaxing drugs Nitrates
TZP-101
R137696 M1/M2 muscarinic receptor blockers
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Acotiamide (Z338, YM443)
Controlled studies: no benefit over placebo
Phase 2 in FD: no benefit over placebo
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induced satiety [3]. However, intranasal administration of the drug failed to induce a significant relaxation in healthy volunteers, probably owing to lower bio-availability [64]. As mentioned above, 5-HT4 receptor agonists may enhance gastric accommodation through the activation of presynaptic receptors [12,19,22]. Furthermore, the 5HT3 agonist MKC-733 induced gastric relaxation in healthy volunteers, but this may have occurred as a consequence of nausea [65].
targets and optimized trial design for the treatment of this common clinical problem (Figure 1, Table 1).
An alternative way to promote gastric accommodation is inhibition of excitatory motor neurons, which are mainly cholinergic. This can be achieved through activation of presynaptic inhibitory a2 receptors or 5-HT1A receptors, or through inhibition of presynaptic muscarinic receptors [7]. Buspirone, a 5-HT1A receptor agonist with anxiolytic properties dose-dependently enhances gastric accommodation and delays gastric emptying in man [66]. R-137696, a newly developed 5-HT1A receptor agonist, also dosedependently relaxes the proximal stomach in man [67]. A placebo-controlled multi-center study failed to show any symptomatic benefit during a four-week treatment with R-137696 in FD, possibly owing to desensitization [68]. Presynaptic a2-receptors are present on intrinsic cholinergic nerve endings in the stomach, and acute administration of the a2-agonist clonidine enhanced gastric accommodation [69]. To date, no clinical studies with clonidine in FD are available.
1.
Tack J: Gastric motor disorders. Best Pract Res Clin Gastroenterol 2007, 21:633-644.
2.
Vantrappen G, Janssens J, Hellemans J, Ghoos Y: The interdigestive motor complex of normal subjects and patients with bacterial overgrowth of the small intestine. J Clin Invest 1977, 59:1158-1166.
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Tack J, Piessevaux H, Coulie B, Caenepeel P, Janssens J: Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology 1998, 115:1346-1352.
4.
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Z-338 (acotiamide) is a novel compound that enhances acetylcholine release via antagonism of the M1 and M2 muscarinic receptors [70]. In a pilot study, acotiamide showed potential to improve FD symptoms and quality of life, through a mechanism that may involve enhanced accommodation [71]. In an animal model, acotiamide reversed stress-induced delayed gastric emptying and feeding inhibition, through inhibition of stress-induced gene expression in the hypothalamus and the medulla oblongata [72]. Preliminary reports of phase 2 programs with acotiamide in the US and in Japan confirmed ifs therapeutic potential [73].
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest
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10. Karamanolis G, Caenepeel P, Arts J, Tack J: Determinants of symptom pattern in idiopathic severely delayed gastric emptying: gastric emptying rate or proximal stomach dysfunction? Gut 2007, 56:29-36. 11. Moayyedi P, Soo S, Deeks J, Delaney B, Innes M, Forman D: Pharmacological interventions for non-ulcer dyspepsia. Cochrane Database Syst Rev 2006, 18:CD001960. 12. Karamanolis G, Tack J: Promotility medications—now and in the future. Dig Dis 2006, 24:297-307.
Conclusion Currently available agents for treatment of gastric motility disorders include several different classes of agents. Abilities to enhance gastric emptying or to enhance gastric accommodation have been identified as putatively relevant underlying pharmacodynamic mechanisms. Effective drug development for gastric motor disorders is hampered by pathophysiological heterogeneity of the patient population, by a lack of well-accepted endpoints, and by an inconsistent relationship between changes in motor function and symptomatic outcome. Nevertheless, a number of phase 2 trials have shown symptomatic benefit with selected agents. Experience from these studies is likely to lead to better identification of relevant Current Opinion in Pharmacology 2008, 8:690–696
13. Talley NJ, Verlinden M, Snape W, Beker JA, Ducrotte P, Dettmer A, Brinkhoff H, Eaker E, Ohning G, Miner PB et al.: Failure of a motilin receptor agonist (ABT-229) to relieve the symptoms of functional dyspepsia in patients with and without delayed gastric emptying: a randomized double-blind placebocontrolled trial. Aliment Pharmacol Ther 2000, 14:1653-1661. 14. De Maeyer JH, Lefebvre RA, Schuurkes JA: 5-HT4 receptor agonists: similar but not the same. Neurogastroenterol Motil 2008, 20:99-112. Comprehensive review of different classes of 5-HT4 agonists and their respective pharmacological properties. 15. Beattie DT, Smith JA, Marquess D, Vickery RG, Armstrong SR, Pulido-Rios T, McCullough JL, Sandlund C, Richardson C, Mai N, Humphrey PP: The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2b receptor antagonist in vitro and in vivo. Br J Pharmacol 2004, 143:549-560. 16. Tack J, Mu¨ller-Lissner S, Bytzer P, Corinaldesi R, Chang L, Viegas A, Schnekenbuehl S, Dunger-Baldauf C, Rueegg P: A www.sciencedirect.com
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