Models of Emesis

3 Ondansetron

4 Granisetron

6.30.3.2 Models of Gastrointestinal Motility

Many animal models of GI motility have been described in the literature and have been used to illustrate the prokinetic activity of many of the pharmacological classes reviewed below. Nonmammalian models of GI motility suitable for the evaluation of new chemical entities (NCEs) effects are scarce. However recent studies of intestinal motor activity in the zebrafish (Danio rerio) and the nematode worm (Caenorhabditis elegans) raise the possibility of studying intestinal physiology in species that are highly manipulable at the genetic level and may be utilized in high-throughput experimental systems. The most commonly used species in motility research are the rat and the dog, although murine models have been developed that facilitate the study of GI motility in transgenic animals. When selecting an animal species in which to study the effects of NCEs, the relevance of the species to the human should be considered. For example, the anatomy of the rat stomach is quite different from that of the human, in having a defined fore-stomach that is quite different in structure, and probably function, from the human gastric fundus. The rat also lacks a structural equivalent to the human rectum and thus lacks the storage and control of continence offered by the human large bowel. Similarly the intestine, and in particular the colon, of the dog is considerably shorter than in the human and is in keeping with the largely carnivorous habits of this species. In this species the upper GI tract is considered a good model for the human whereas the lower GI tract may be less of a good model.

The effect of NCEs on gastric emptying has been widely studied and several experimental models have been established in a range of species. The most basic models involve the oral gavage of test meals and subsequent recovery of the gastric contents following euthanization of the animals. This type of model is only realistically applicable to rodents and is limited because it does not allow repeat observations in the same animals. This basic model has been adapted to allow recovery of a test meal, sometimes containing nonabsorbable markers, from artificial fistulae into the stomach or the duodenum. This model has been established in dogs but has not been widely adopted. The ideal model for use in higher animal species requires minimally invasive procedures and ideally is based on similar clinical experimental paradigms. This type of model offers the opportunity for establishing models with the greatest potential for translating across species from animals to human. Such models have been established for measuring gastric emptying.1 In one such model, acetaminophen is included in the test meal and the appearance of this marker is measured in the systemic circulation. This model relies on the absorption of paracetamol/acetaminophen in the proximal regions of the duodenum as an indirect marker of gastric emptying and this model has been shown to be sensitive to drug effects. Another model of gastric emptying that is a direct correlate of a human model has been developed. In this model radioisotopes of indium and technetium are used to separately label liquids and solids and enable simultaneous monitoring of their egress from the stomach using gamma scintigraphy. One model that has been developed for use in animals, following its successful use in clinical research, relies on the metabolism of octanoate. In this method, rats or dogs are fed meals containing octanoate labeled with 13C. Gastric emptying is calculated from the area under the curve of the cumulative excretion of 13CO2, collected from the expired air. This model has been shown to be sensitive to the effects of prokinetic agents. A challenge for gastric emptying models is that the baseline rate of emptying, especially of liquids, can be extremely rapid, making it extremely difficult to demonstrate a prokinetic effect of an investigational drug. An option for overcoming this is to slow the baseline rate of emptying, which can be achieved either pharmacologically or physiologically. Pharmacological slowing of gastric emptying, can be achieved by the administration of many endogenous GI hormones, such as cholecystokinin (CCK) or neuropeptide Y/peptide YY (NPY/PYY) or by pharmacologic agents such as morphine or clonidine. Such models have been well established in the literature and have proven useful in demonstrating prokinetic activity. The rate of gastric emptying can also be profoundly influenced by the composition of a test meal; for example, high-fat meals are emptied more slowly than ones containing lower levels of fat. However, meal composition can influence the effect of drugs under test as, for example, with 5HT3 receptor antagonists. These agents have little or no effect on rates of gastric emptying in most models but appear to accelerate gastric emptying in models using high-fat test meals. Fat retards gastric emptying through a mechanism involving the release of 5HTand the activation of 5HT3 receptors on vagal afferent neurons. Thus 5HT3 receptor antagonists can inhibit the retardation of gastric emptying induced by fat and thus appear as prokinetic agents, which is unlikely to be the case in any clinically meaningful sense.

In studying the effects of NCEs on intestinal motor function, investigators have utilized many approaches to monitor either motor activity directly or the transit of material along sections of the GI tract. Direct measurement of motor function, irrespective of the region of the GI tract under investigation, relies on the placement of strain gages on the intestinal serosa to measure contractile activity. Alternatively, measurement of patterns of electrical activity in the wall of the intestine have been made via the placement of electromyographic electrodes. Historically these techniques have required the physical connection of these strain gauges or electrodes to external recording equipment, which has necessitated at least partial restriction of the animals' movements and behavior. The development of telemetric methodologies allows long-term recordings of intestinal motility in free-living animals. The study of intestinal transit can be achieved either by identifying waves of orthograde and retrograde propulsive activity from motility recording at multiple sites along the intestine or by monitoring the passage of material along the intestine, either directly or indirectly. Both methodologies have strengths and weaknesses. The use of motility recordings to infer the passage of material is laborious and is prone to misinterpretation as not all contractile activity is associated with propulsion but rather can be involved in mixing intestinal contents. However, this type of record has the advantage of being a direct measurement of intestinal motor activity. The measurement of intestinal transit has been achieved using radioactive tracers, in which the 'center of gravity' of a radioactive meal is determined, or nonabsorbable marker such as charcoal, in which the leading edge of the charcoal is visualized. Both these methodologies are terminal procedures, as they require the animals to be euthanized for the data to be extracted. Noninvasive methodologies are clearly preferred and have been developed. The oral administration of the nonabsorbable carbohydrate lactulose, results in an increase in hydrogen in the exhaled breath. This occurs only when lactulose is metabolized by colonic bacteria and so can be used as an indirect measurement of orocecal transit. Fluoro- or radiometric methods have been developed to enable the measurement of large bowel transit. In these methodologies the passage of either a radioactive tracer or nonabsorbable radioopaque markers are monitored using a gamma camera or x-ray apparatus.

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