184.108.40.206 Gastrointestinal Motility Disorders and Prokinetics of the gastric fundus by intragastric gas. Pressure on the fundus triggers ascending intermural reflexes that result in relaxation of the LES. The benefit from prokinetic agents may result from the reduction in either pressure on the fundus or in the adaptive relaxation of the fundus in response to ingestion of food, which results from reductions in gastric retention.
A challenge encountered in the search for new antiemetic agents comes with the selection of a suitable experimental model. The most commonly used laboratory animal species do not possess an emetic reflex (e.g., mice, rats, guinea pigs, and rabbits) and will not vomit to any human emetogen. The most commonly used animal species in emesis research are the ferret and the dog, which have been studied widely. In addition models of emesis have been established in the cat, the monkey, the pigeon, and more recently in an insectivore, the house musk shrew.
Experimentally, the ferret has been shown to vomit to all human emetogens studied, including cisplatin, cyclophosphamide, x-irradiation, ipecacuanha, and hyperosmolar saline. Unlike human, the ferret will demonstrate a prolonged and substantial period of retching ahead of a vomiting episode, unlike the human, where only one or two retches will normally precede vomiting. This acute model of vomiting has been adapted to study the phenomenon of delayed emesis. In humans, nausea and vomiting can persist long after the original emetic stimulus has been given and compared to the initial, acute response, this has been problematic to control. In the ferret, lower doses of chemotherapeutic agents have been employed to provoke an emetic response that is prolonged and emesis has been observed for up to 24 h after administration of the emetogen. The usefulness of the ferret in the discovery and development of significant new antiemetic agents has been demonstrated with the discovery of the 5HT3 receptor antagonists, such as ondansetron (3) and granisetron (4). The dog has the longest pedigree in emesis research, having been used for many of the neurophysiologic studies that defined the emetic pathway in the 1950s and 1960s. The dog has been shown to respond to many of the same emetogens, often being highly sensitive to them, and to be susceptible to the blocking effects of antiemetics. However, since that time the dog has not been used as extensively, most probably for ethical questions raised by the terminal nature of many of the studies with radiation and chemotherapeutic agents. Other species have been used less frequently. The cat has been studied in motion-induced emesis, but in common with higher mammals, complex three-dimensional movement is required to evoke an emetic response. It is against this background that one of the smallest animals capable of demonstrating an emetic response was identified, the house musk shrew (Suncus murinus). In addition to demonstrating retching and vomiting to all emetogenic stimuli studied, this animal is sensitive to motion-induced emesis. In this case, the motion stimulus can be a simple two-dimensional one, which is simpler to apply than that required for other species. When selecting an animal model, one needs to understand the translational value of each model in terms of sensitivity and response to emetic stimuli, the pharmacology of the receptor under investigation in that species, and the behavior of the investigational drugs under study in the species selected.
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