Fabrizio De Ponti

Functional Gut Disorders: From Motility to Sensitivity Disorders. A Review of Current and Investigational Drugs for Their Management

Functional gut disorders include several clinical entities defined on the basis of symptom patterns (e.g., functional dyspepsia, irritable bowel syndrome, functional abdominal pain, functional abdominal bloating), for which there is no established pathophysiological mechanism. Because there is no well-defined pathophysiological target, treatment should be aimed at symptom improvement. Prokinetics and antispasmodics have been widely used in the treatment of functional gut disorders on the assumption that disordered motility is the underlying cause of symptoms, and symptom improvement is indeed achievable with these compounds in some, but not all, patients with features of hypo- or hypermotility, respectively. In the first part of this review, we cover the basic pharmacology and discuss the rationale for the clinical use of prokinetics and antispasmodics. On the other hand, in the past few years, the explosive growth in the research focusing on visceral sensitivity and visceral reflexes has suggested that at least some patients with functional gut disorders have altered visceral perception. Thus, the second part of the review covers these developments and focuses on studies addressing the issue of drugs modulating visceral sensitivity.

Functional evidence of atypical β3‐adrenoceptors in the human colon using the β3‐selective adrenoceptor antagonist, SR 59230A

The role of β3‐adrenoceptors in human colonic circular smooth muscle was assessed in vitro by use of the β2‐selective antagonist SR 59230A. Isoprenaline, in the presence of the selective β‐adrenoceptor antagonists CGP 20712A (β1) and ICI 118551 (β2), both at 0.1 μ, concentration‐dependently relaxed the preparation (pEC50 = 5.22). This effect was potently and competitively antagonized by SR 59230A with a pA2 of 8.31, while its R,R enantiomer SR 59483A gave an apparent pKB of 6.21. Relaxation was likewise produced by CGP 12177A (pEC50 = 6.05), but not by BRL 37344. Although only one of these β3‐selective agonists was effective, the remarkably high potency of SR 59230A as a stereospecific antagonist of non‐β1 non‐β2 relaxation of human colonic muscle by isoprenaline provides strong functional evidence of β3‐adrenoceptors in that tissue.

Adrenergic mechanisms in the control of gastrointestinal motility: From basic science to clinical applications

Over the years, a vast literature has accumulated on the adrenergic mechanisms controlling gut motility, blood flow, and mucosal transport. The present review is intended as a survey of key information on the relevance of adrenergic mechanisms modulating gut motility and will provide an outline of our knowledge on the distribution and functional role of adrenoceptor subtypes mediating motor responses. alpha1-Adrenoceptors are located postsynaptically on smooth muscle cells and, to a lesser extent, on intrinsic neurons; alpha2-adrenoceptors may be present both pre- and postsynaptically, with presynaptic auto- and hetero-receptors playing an important role in the modulation of neurotransmitter release; beta-adrenoceptors are found mainly on smooth muscle cells. From a clinical standpoint, adrenoceptor agonists/antagonists have been investigated as potential motility inhibiting (antidiarrheal/antispasmodic) or prokinetic agents, although at present their field of application is limited to select patient groups.

Immunological Adverse Effects of Anticonvulsants: What is their Clinical Relevance?

SummaryLong term administration of anticonvulsants is sometimes associated with impairment of the humoral and/or cellular immune response. Furthermore, certain well known adverse reactions to antiepileptics may have an immunotoxicological origin e.g. lymphadenopathy, pseudolymphoma and systemic lupus erythematosus. However, two important questions remain unresolved. First, the possibility that epilepsy per se might be primarily associated with immune alterations makes it difficult to assess the pathogenetic role of a specific drug, especially in a patient population usually on multiple drug therapy. Secondly, the clinical relevance of some of the observed immunological abnormalities is still highly controversial.This review is intended to give an outline of the present state of knowledge on the effects of anticonvulsants on humoral, cellular and nonspecific immunity, with particular regard to some of the major clinical conditions that have been ascribed to drug-induced immune dysregulation, such as pseudolymphoma and systemic autoimmune diseases. The immunotoxic potential of anticonvulsants appears to be low, and immunological monitoring is not usually required except in patients with known immune defects.

N-Methyl-di-aspartate receptors modulate neurotransmitter release and peristalsis in the guinea pig isolated colon ☆

To assess the role of NMDA receptors in modulating neurotransmitter release in the myenteric plexus, we studied the effects of L-glutamic acid and NMDA on endogenous acetylcholine and noradrenaline overflow (assayed by HPLC) from the guinea pig isolated distal colon. L-Glutamic acid and NMDA enhanced electrically evoked acetylcholine and noradrenaline overflow and these effects were reversed by selective NMDA receptor antagonists. The possible functional significance of these findings was studied by measuring the efficiency of the colonic peristaltic reflex in the presence of NMDA receptor agonists. NMDA inhibited propulsion velocity at all concentrations tested, this effect being antagonized by (+/-)-2-amino-5-phosphonopentanoic acid and virtually abolished in sympathetically denervated animals. In conclusion, the inhibitory effect of NMDA on peristalsis, being almost entirely dependent on the integrity of sympathetic pathways, could be, at least in part, due to NMDA-induced noradrenaline release.

Calcium-channel blockers and gastrointestinal motility: Basic and clinical aspects

Several calcium-channel blockers currently in use for the treatment of cardiovascular disorders have recently been tested for their effects on gastrointestinal motility. The rationale for this approach centers on the concept that calcium-channel blockers are at least as potent in inhibiting intestinal smooth muscle as in relaxing vascular smooth muscle. This review will give an outline of the most recent findings on the role of calcium and calcium channels in smooth muscle and neuronal function in the digestive system. It will also consider the mechanisms by which calcium-channel blockers may affect gastrointestinal motility and assess potential clinical applications in gastroenterology. The main goal for researchers in this field will be the development of gut-selective agents, with no cardiovascular side effects.

Functional Evidence for the Presence of β3-Adrenoceptors in the Guinea Pig Common Bile Duct and Colon

To determine the existence of beta 3-adrenoceptors in functional assays in isolated preparations for which data are lacking, we compared the effects of SR 58611A, a selective beta 3-adrenoceptor agonist, and isoprenaline in the guinea pig common bile duct, distal colon and urinary bladder. SR 58611A and isoprenaline relaxed the common bile duct (EC50: 6.85 and 0.41 mumol/l, respectively). The effect of SR 58611A was resistant to CGP 20712A, ICI 118551, propranolol and tetrodotoxin, but was antagonized by alprenolol (pA2 = 6.86), while the effect of isoprenaline was antagonized by CGP 20712A, ICI 118551, propranolol and alprenolol (pA2 = 7.04, in the presence of propranolol to saturate beta 1- and beta 2-adrenoceptors). In colonic preparations, SR 58611A and isoprenaline relaxed circular muscle strips (EC50: 5.48 and 0.49 mumol/l, respectively). The effect of SR 58611A was resistant to CGP 20712A, ICI 118551, propranolol and tetrodotoxin, but was antagonized by alprenolol (pA2 = 7.01). The effect of isoprenaline was resistant to CGP 20712A, but was antagonized by ICI 118551, propranolol and alprenolol (pA2 = 6.88, in the presence of propranolol). In urinary bladder strips, SR 58611A had no effect, whereas isoprenaline reduced resting tone (EC50:0.87 mumol/l), an effect antagonized by alprenolol (pA2 = 8.14). These data provide functional evidence for the presence of beta 3-adrenoceptors in the guinea pig common bile duct and colon, but not in the urinary bladder. At the concentrations used, the effect of SR 58611A was probably mediated solely by activation of beta 3-adrenoceptors located on smooth muscle cells, whereas the effects of isoprenaline were due to beta 3- and also to beta 1-and/or beta 2-adrenoceptor activation.

Inhibitory effects of calcium channel blockers on intestinal motility in the dog.

Calcium channel blockers are now widely used for the treatment of cardiovascular disorders. However, data concerning their effects on intestinal motility in vivo are still rather fragmentary. Therefore, we evaluated the effects of three prototype calcium channel blockers (nifedipine, verapamil and diltiazem) on intestinal motility in five fasting, conscious dogs fitted with electrodes and strain-gauges along the small bowel. The myoelectric data were analyzed by a recently developed and validated computer program which allows accurate monitoring of intestinal spike activity. The mechanical data were analyzed by calculating a motility index. After recording of at least two migrating motor complexes (control), an i.v. infusion of one of the following calcium channel blockers was maintained for 3 h: 0.29 or 0.87 mumol/kg per h nifedipine, 1.02 or 2.04 mumol/kg per h verapamil and 1.11 or 2.22 mumol/kg per h diltiazem. Nifedipine 0.29 mumol/kg per h significantly reduced (P less than 0.05) spike activity and motility index during phases II and III without disrupting migrating motor complex cycling. The higher dose suppressed migrating motor complex cycling and almost completely abolished both spike and mechanical activities. The two doses of verapamil had effects similar to those of the two doses of nifedipine. Both doses of diltiazem significantly reduced (P less than 0.05) spike activity and motility index during phases II and III without disrupting migrating motor complex cycling. We conclude that all the agents tested, apart from their well known cardiovascular effects, also have a profound inhibitory effect on intestinal motility in vivo, the order of potency being nifedipine greater than verapamil greater than diltiazem. The search for more selective calcium channel blockers for the treatment of intestinal motor disorders with minimal cardiovascular effects is warranted.

IN VIVO CHARACTERIZATION OF THE COLONIC PROKINETIC EFFECT OF ERYTHROMYCIN IN THE RABBIT

The motor effect of erythromycin was characterized in conscious rabbits chronically fitted with electrodes and strain-guage force transducers implanted along the proximal and distal colon. Fecal pellet output was also evaluated as an index of propulsive activity. In order to get an insight into the pathways involved in mediating the effect of erythromycin, the macrolide was also administered after pretreatment with atropine, nifedipine or ondansetron. Furthermore, in vitro experiments with erythromycin alone and in the presence of atropine, nifedipine, tetrodotoxin or ondansetron were carried out with circular muscle strips taken from rabbit distal colon. In vivo, erythromycin (0.087-5.6 mg/kg i.v. bolus) dose-dependently stimulated spike and mechanical activities at both colonic levels, with a more marked effect on the distal colon. Erythromycin also dose-dependently increased the number of aborally migrating long spike bursts and fecal pellet output. The reproducibility of the response to erythromycin was confirmed by experiments with the dose of 2.8 mg/kg i.v. bolus, repeated in five consecutive experiments at 48-hour intervals. Nifedipine, but not atropine or ondansetron, significantly reduced the colonic motor response to erythromycin. In vitro experiments gave results in line with the in vivo data: the concentration-dependent contractile effect of erythromycin was almost suppressed by nifedipine, but resistant to atropine, tetrodotoxin or ondansetron. In conclusion, this study provides evidence that: (1) erythromycin is a prokinetic drug at the colonic level in rabbits, and (2) both in vivo and in vitro, the effects of erythromycin are exerted at the smooth muscle level by mechanisms depending on influx of extracellular calcium, while muscarinic and 5-HT3 receptors are not involved, at least in this model.

Novel therapeutic strategies in acid-related disorders

Acid-related disorders of the upper gut encompass diseases of the oesophagus, stomach and duodenum, such as gastro-oesophageal reflux disease (GORD), gastric and duodenal (peptic) ulcers, Zollinger–Ellison syndrome and iatrogenic ulcers and gastrointestinal bleeding mostly induced by non-steroidal anti-inflammatory drugs (NSAIDs). Gastric acid and pepsin are largely involved in their pathophysiology, both factors acting with Helicobacter pylori (especially in peptic ulcers) or with either NSAIDs, stress or smoking. All these diseases can benefit from agents that neutralise gastric acid or inhibit its secretion. Neutralising acid with antacids or decreasing acid secretion with histamine H2-receptor antagonists (H2-RAs) was the standard of care before the introduction of proton pump inhibitors (PPIs), which have been one of the major advances in the field of gastrointestinal pharmacology. Their superior efficacy in acid-related disorders with respect to other acid reducing drugs is now widely recognised. PPIs are also used to control atypical GORD symptoms, such as laryngitis, asthma and cough associated with reflux. In spite of their clinical efficacy in a number of conditions, the emerging need for new therapeutic approaches, such as ‘on-demand’ treatment for GORD symptoms, requires some features (e.g., fast onset of action at day 1 with an acid suppressant effect throughout the day and night, to avoid the nocturnal acid breakthrough) that currently available PPIs only partially achieve. Moreover, a subset of patients with GORD still do not respond to the available therapeutic regimens. Novel agents (or novel formulations of available PPIs) have recently been patented to try to overcome these problems.