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Emesis
Published in Michael JG Farthing, Anne B Ballinger, Drug Therapy for Gastrointestinal and Liver Diseases, 2019
Gareth J Sanger, Paul LR Andrews
In partial obstruction, particularly when related to a motor disorder or when drug-induced, there is a clear logic to inhibiting the nausea by using drugs that facilitate aboral gastrointestinal propulsion; efficacy, however, is unpredictable.62 Cisapride or metoclopramide increase gut motility by partially activating the 5-HT4 receptor and facilitating the cholinergic motor pathways within the peristaltic reflex; the affinity and lack of selectivity of these drugs for the 5-HT4 receptor is well-documented59, 63 (see Table 3.3 for metoclopramide). An example of their use is a continuous subcutaneous infusion of metoclopramide to relieve ‘narcotic bowel syndrome’.
Incapacitating Agents and Technologies: A Review *
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Fentanyl, N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl] propanamide, and its analogs are narcotic analgesics and anesthetics, which act as opiate agonists. They have high lipid solubility and penetrate the blood–brain barrier easily, rapidly producing analgesia, euphoria, miosis, and respiratory depression. The depression of breathing is caused by direct inhibition of rhythm-generating respiratory neurons in the pre-Boetzinger complex of the brain stem. Selective activation of 5-hydroxytryptamine 4(a) receptors in this area by 5-HT4 receptor agonists abolishes the opiate-induced respiratory depression without loss of analgesic effect. Dissociation of the respiratory depression effect from the opiate-induced sedative effect can be accomplished by the use of antagonists such as naloxone, naltrexone, and nalmefene (Salem et al., 2005a). Fentanyls have been used as drugs of abuse. Human volunteer studies using low i.v. doses have shown that fentanyl produces impaired coordination, dysphoria, and somatic symptomatology, with a transient liking for the experience (Zacny et al., 1992).
Autonomic dysfunction
Published in Jeremy Playfer, John Hindle, Andrew Lees, Parkinson's Disease in the Older Patient, 2018
Cisapride, a prokinetic agent, was effective for constipation in PD,78 but is currently unavailable because of an associated risk of cardiac conduction defects. Alternative prokinetic agents include domperidone and the new 5-HT4 receptor agonists, tegaserod and mosapride citrate. Domperidone is an effective prokinetic agent in the upper gastrointestinal tract,79 but has been shown to have little effect on the lower gastro intestinal slow transit times in PD. The 5-HT4 receptor agonists facilitate intestinal motility by facilitating release of acetylcholine from enteric cholinergic neurons. A small study in patients with MSA and PD has suggested a beneficial effect of mosapride on constipation.80
Gastroparesis syndromes: emerging drug targets and potential therapeutic opportunities
Published in Expert Opinion on Investigational Drugs, 2023
Le Yu Naing, Matthew Heckroth, Prateek Mathur, Thomas L Abell
The 5-HT4 receptor is a G-protein linked receptor that promotes the activation of the adenyl cyclase/cyclic adenosine monophosphate (cAMP)/protein kinase A pathway enhancing cell excitability[29]. Activation of these receptors on myenteric cholinergic nerve terminals induces the release of several neurotransmitters that promote propulsive motility and produce coordinated contraction and relaxation of gastrointestinal smooth muscle[32]. They have also been shown to play a role in inhibiting visceral pain and suppressing intestinal hypersensitivity in response to distension. 5-HT4 receptor agonists are used clinically as a prokinetic agent for patients with gastroparesis. Cisapride, a potent 5-HT4 agonist, and tegaserod, a partial 5-HT4 agonist, were both shown to be effective at relieving Gp symptoms as well as accelerating gastric emptying and colonic transit. However, both were withdrawn from the US market secondary to reports of serious cardiac arrhythmias related to QT interval prolongation. Tegaserod is now available with limited access in the US[33].
New investigational agents for the treatment of major depressive disorder
Published in Expert Opinion on Investigational Drugs, 2022
Bartłomiej Pochwat, Anna Julia Krupa, Marcin Siwek, Bernadeta Szewczyk
In contrast to 5-HT4 receptor stimulation, the activation of 5-HT7 receptors induce the opposite effect. In vitro studies show that stimulation of 5-HT7 receptors led to the remodeling of dendritic spine morphology, promoting the development of immature spines with smaller heads and longer necks [112,113] (Figure 2). 5-HT7 receptor KO mice showed antidepressant phenotype in the FST and TST and antidepressant-like phenotype in CUS model [112,114,115]. These results suggest that the blockade of 5-HT7 receptors should induce antidepressant effects. Unfortunately, there are not too many studies devoted to the antidepressant-like activity of 5-HT7 antagonists. The SB 269970 5-HT7 receptor antagonist showed antidepressant-like activity in naive mice in the FST and TST [116]. Moreover, intrahippocampal administration of SB 269970 reduced immobility time in the FST in naive rats [117]. Preclinical studies on the antidepressant-like activity of 5-HT7 receptor antagonists are sparse, especially those conducted in animal models of depression. However, conclusions drawn from the invitro paradigms indicate that blockade of this receptor could be interesting, making this receptor an attractive pharmacological target.
Drugs under development for the treatment of functional dyspepsia and related disorders
Published in Expert Opinion on Investigational Drugs, 2019
Jan Tack, Imke Masuy, Karen Van Den Houte, Lucas Wauters, Jolien Schol, Tim Vanuytsel, Alain Vandenberghe, Florencia Carbone
Another class of prokinetic agents are the serotonin-4 (5-HT4) receptor agonists. The first 5-HT4-receptor agonist used for treating gastric motility disorders was metoclopramide, which is also a D2-receptor antagonist, but which received a black box warning for its risk of inducing extrapyramidal symptoms [15]. Cisapride, a 5-HT4-receptor agonist developed in the 1990s, became the leading prokinetic drug for the treatment of upper gastrointestinal hypomotility disorders but was withdrawn from the market for its arrhythmogenic potential, due to its affinity for the human ether-a-gogo (HERG) channel [20]. Several other, more selective, 5-HT4 receptor agonists have been developed, including mosapride, tegaserod, prucalopride and velusetrag [8,15,20,21]. Mosapride is used as a prokinetic agent in many Asian countries, but a controlled trial in Europe failed to show efficacy in FD [15]. Both for itopride (see above) and mosapride, differences were observed between Western and Asian studies. While these may reflect differences in patient selection and choice of endpoints, a review of the recent literature indicated that PDS is a more prevalent subtype in Asia, and that GERD co-morbidity is significantly higher in the West [22]. The latter may, in theory, contribute to a lesser efficacy signal of prokinetic therapies focusing on the stomach in Western FD studies.