Metoclopramide for the treatment of diabetic gastroparesis.

Introduction: Gastroparesis is a chronic disorder of the stomach characterized by delayed gastric emptying without mechanical obstruction. Diabetes is the most commonly known cause of gastroparesis. Management of diabetic gastroparesis involves lifestyle modifications, glycemic control, pharmacological drugs, and for refractory cases surgical treatments. Metoclopramide remains the only drug approved by the Food and Drug Administration for diabetic gastroparesis. The aim of this article is to provide a concise review of the pharmacology, clinical efficacy and tolerability of metoclopramide. Areas covered: We searched PubMed using the key words 'metoclopramide', 'diabetic gastroparesis', and 'gastric emptying'. The relevant articles and their bibliography were reviewed. Metoclopramide acts on several different receptors; primarily as a dopamine receptor antagonist, both peripherally improving gastric emptying, and centrally resulting in an anti-emetic effect. Metoclopramide side effects, mostly related to its ability to cross the blood-brain barrier, include drowsiness, restlessness, hyperprolactinemia, and tardive dyskinesia (TD), a movement disorder that may be irreversible. Expert opinion: Metoclopramide carries a black box warning for use >12 weeks due to the risk of TD. However, gastroparesis patients experience chronic symptoms often requiring prolonged treatments. Physicians and patients look forward to FDA approval of new agents for gastroparesis with better efficacy and safety profile.

Upper gastrointestinal sensitivity to meal-related signals in adult humans - relevance to appetite regulation and gut symptoms in health, obesity and functional dyspepsia.

Both the stomach and small intestine play important roles in sensing the arrival of a meal, and its physico-chemical characteristics, in the gastrointestinal lumen. The presence of a meal in the stomach provides a distension stimulus, and, as the meal empties into the small intestine, nutrients interact with small intestinal receptors, initiating the release of gut hormones, associated with feedback regulation of gastrointestinal functions, including gut motility, and signaling to the central nervous system, modulating eating behaviours, including energy intake. Lipid appears to have particularly potent effects, also in close interaction with, and modulating the effects of, gastric distension, and involving the action of gut hormones, particularly cholecystokinin (CCK). These findings have not only provided important, and novel, insights into how gastrointestinal signals interact to modulate subjective appetite perceptions, including fullness, but also laid the foundation for an increasing appreciation of the role of altered gastrointestinal sensitivities, e.g. as a consequence of excess dietary intake in obesity, or underlying the induction of gastrointestinal symptoms in functional dyspepsia (a condition characterized by symptoms, including bloating, nausea and early fullness, amongst others, after meals, particularly those high in fat, in the absence of any structural or functional abnormalities in the gastrointestinal tract). This paper will review the effects of dietary nutrients, particularly lipid, on gastrointestinal function, and associated effects on appetite perceptions and energy intake, effects of interactions of gastrointestinal stimuli, as well as the role of altered gastrointestinal sensitivities (exaggerated, or reduced) in eating-related disorders, particularly obesity and functional dyspepsia.

A pilot study to evaluate the effect of splanchnic nerve stimulation on body composition and food intake in rats.

BACKGROUND: Systemic sympathetic stimulation with caffeine and ephedrine increased metabolic rate, reduced food intake, and improved body composition but had systemic adverse events. We hypothesize that selective sympathetic stimulation of the upper gastrointestinal tract will preserve the advantages of systemic sympathetic stimulation without its adverse events. This study evaluated the effect of splanchnic nerve stimulation on metabolic rate, food intake, and body composition. METHODS: Sixteen Sprague Dawley rats had monopolar electrodes placed on the superior common splanchnic nerve innervating the celiac ganglia. An indifferent electrode was placed subcutaneously on the back. The animals were placed on a 60% fat diet, and eight rats were stimulated for 6 weeks. The stimulation was advanced over 3 days from 0.6 mA to 3 mA. Metabolic rate and food intake were measured daily; weight change was monitored weekly, and body composition was determined by nuclear magnetic resonance (NMR) at the end of the study. Four of the eight animals had metabolic rate measured three times over 2-day periods at 0 mA, 1 mA, and 3 mA of stimulation in a metabolic chamber. RESULTS: Except for the first week of stimulation, there was no difference in body weight between the stimulated and control groups. Cumulative food intake was less in the stimulated group (p<0. 001). The lean-to-fat ratio was greater in the stimulated group (p<0. 01), and the animals that received incremental stimulation showed significantly augmented metabolic rate (p<0. 02). CONCLUSIONS: Splanchnic nerve stimulation decreased food intake, increased metabolic rate, and improved body composition.

Stimulation of sympathetic innervation in the upper gastrointestinal tract as a treatment for obesity.

Sympathetic activity and obesity have a reciprocal relationship. Firstly, hypothalamic obesity is associated with decreased sympathetic activity. Caffeine and ephedrine increase sympathetic activity and induce weight loss, of which 25% is due to increased metabolic rate and 75% is due to a reciprocally decreased food intake. Secondly, hormones and drugs that affect body weight have an inverse relationship between food intake and metabolic rate. Neuropeptide Y decreases sympathetic activity and increases food intake and body weight. Thirdly, a gastric pacemaker Transcend and vagotomy increase the ratio of sympathetic to parasympathetic activation, decrease food intake, and block gut satiety hormones. Weight loss with the pacemaker or vagotomy is variable. Significant weight reduction is seen only in a small group of those treated. This suggests that activation of the sympathetic arm of the autonomic nervous system may be most important for weight loss. Systemic sympathetic activation causes weight loss in obese patients, but side effects limited its use. We hypothesize that selective local electrical sympathetic stimulation of the upper gastrointestinal tract may induce weight loss and offer a safer, yet effective, obesity treatment. Celiac ganglia delivers sympathetic innervation to the upper gastrointestinal tract. Voltage regulated electrical simulation of the rat celiac ganglia increased metabolic rate in a dose-dependent manner. Stimulation of 6, 3, or 1.5 V increased metabolic rate 15.6%, 6.2%, and 5%, respectively in a single rat. These responses support our hypothesis that selective sympathetic stimulation of the upper GI tract may treat obesity while avoiding side effects of systemic sympathetic activation.

Anatomy and physiology of feeding and swallowing: normal and abnormal.

Eating and swallowing are complex behaviors involving volitional and reflexive activities of more than 30 nerves and muscles. They have two crucial biologic features: food passage from the oral cavity to stomach and airway protection. The swallowing process is commonly divided into oral, pharyngeal, and esophageal stages, according to the location of the bolus. The movement of the food in the oral cavity and to the oropharynx differs depending on the type of food (eating solid food versus drinking liquid). Dysphagia can result from a wide variety of functional or structural deficits of the oral cavity, pharynx, larynx, or esophagus. The goal of dysphagia rehabilitation is to identify and treat abnormalities of feeding and swallowing while maintaining safe and efficient alimentation and hydration.

Dopaminergic control of foregut contractions in Locusta migratoria.

Tyrosine hydroxylase-like immunoreactivity is present in cell bodies and processes in the brain and optic lobes of Locusta migratoria, with processes projecting along the frontal connectives to form a neuropile within the frontal ganglion. Immunoreactive cell bodies and processes are also evident in the hypocerebral and ventricular ganglia with processes extending over the foregut. Tyrosine hydroxylase is the rate-limiting enzyme in dopamine biosynthesis, and high-performance liquid chromatography coupled to electrochemical detection was used to confirm the presence of dopamine in the innervation to the foregut. Spontaneous foregut contractions are under the control of the ventricular ganglia and are absent when these ganglia are removed. Dopamine leads to an inhibition of both the amplitude and frequency of phasic contractions of the foregut that are produced when the ventricular ganglia are left attached. Dopamine has direct effects on the foregut muscle in the absence of the ventricular ganglia, inhibiting a proctolin-induced contraction in a dose-dependent manner.

Drugs affecting visceral sensitivity: ready for the prime time?

Visceral sensitivity has been recognized over the last decade as a frequent pathophysiological component of functional bowel disorders. Studies in animals and humans have identified numerous neurotransmitters involved in the processing of sensations from the gut to the brain. However, up to now none of them has actually been proven to have a marked clinical efficacy and the benefit comes rather from their action of bowel disturbances. Reproducible tests are lacking to detect visceral hypersensitivity in humans and distension tests are difficult to undertake in a clinical setting. Therefore, abnormal visceral sensitivity may not be regarded as a tool to select IBS patients as candidates for a given treatment.

Upper gastrointestinal sensory-motor dysfunction in diabetes mellitus.

Gastrointestinal (GI) sensory-motor abnormalities are common in patients with diabetes mellitus and may involve any part of the GI tract. Abnormalities are frequently sub-clinical, and fortunately only rarely do severe and life-threatening problems occur. The pathogenesis of abnormal upper GI sensory-motor function in diabetes is incompletely understood and is most likely multi-factorial of origin. Diabetic autonomic neuropathy as well as acute suboptimal control of diabetes has been shown to impair GI motor and sensory function. Morphological and biomechanical remodeling of the GI wall develops during the duration of diabetes, and may contribute to motor and sensory dysfunction. In this review sensory and motility disorders of the upper GI tract in diabetes is discussed; and the morphological changes and biomechanical remodeling related to the sensory-motor dysfunction is also addressed.

The effects of Calliphora vomitoria Tachykinin-I and the FMRFamide-related peptide Perisulfakinin on female Phormia regina crop contractions, in vitro.

The dipteran crop is an elaborate diverticulation of the foregut that serves as an important food reservoir and feeding regulator. Peptidergic innervation has been associated with the crop of the blow fly Phormia regina and myotropic neuropeptides have been previously demonstrated to affect crop contraction rates, in vitro. The blow fly peptide, callitachykinin-1 was found to increase the rate of contractions and alter the contractile morphology of the P. regina crop, in vitro. The cockroach peptide perisulfakinin, however, had no measurable affect on crop contractions.

Visceral hypersensitivity in functional disorders of the upper gastrointestinal tract.

Visceral hypersensitivity is now recognised as a major pathophysiological mechanism in functional gastrointestinal disorders of the upper gastrointestinal tract. In patients with non-cardiac chest pain and functional dyspepsia, a high prevalence of visceral hypersensitivity has been indeed observed. In these patients, luminal physiological stimuli can be perceived as unpleasant or even painful. Although the fine mechanisms underlying such "aberrant perceptions" are yet not fully clarified, it is thought that an altered activation of the gut-wall receptors, an altered conduction of sensory inputs at the level of neural pathways, or an impaired processing of the sensations at the level of brain, may occur along the brain-gut axis. So far, drugs able to reduce hypersensitivity, that target each of the constituents of the stimuli-perception chain, have the therapeutic potential to reduce visceral hypersensitivity and, thus, to improve the symptoms. In this context, the availability of new agonists/antagonists to neurotransmitters offers a new exciting tool for the treatment of functional disorders of the upper gastrointestinal tract.