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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
To identify which drugs are most effective against different forms of nausea and vomiting, the major causes of emesis have been ‘clustered’ into groups defined by the predominant emetic pathway (Tables 3.1 and 3.2). The tables also indicate the efficacy of selective 5-hydroxytryptamine3 (5-HT3) receptor antagonists, antiemetic drugs that inhibit the ability of the 5-HT released from the intestinal mucosal enterochromaffin cells to activate and sensitize the vagal nerve afferents terminating in close proximity. This pharmacological selectivity is of enormous value in dissecting the pathways and mechanisms by which drugs and diseases evoke emesis. Figure 3.1 summarizes these pathways, linking them to major classes of antiemetic drug receptor. Included in parenthesis are also those drugs that exert an indirect antiemetic activity because they symptomatically alleviate the cause of the nausea or vomiting (e.g. gastric stasis), rather than interfere with the emetic pathways themselves. Such drugs include the glucocorticoids (e.g. dexamethasone), the partial 5-HT4 receptor agonists (e.g. cisapride, metoclopramide), the somatostatin receptor agonist, octreotide and the benzodiazepines. Finally, the locus at which NK1 receptor antagonists might be expected to exert anti-emetic activity is also indicated but, since these compounds are not generally available for clinical use, no further discussion of their potential use is included in this chapter (see reference 9 for mechanisms of action).
Smoking
Published in Clive Handler, Gerry Coghlan, Marie-Anne Essam, Preventing Cardiovascular Disease in Primary Care, 2018
Clive Handler, Gerry Coghlan, Marie-Anne Essam
This is a nicotine receptor agonist. It is available in Europe, the USA and on prescription in the UK. Small studies suggest that it is at least as effective as buproprion. It reduces the urge to smoke and nicotine craving by reducing the nicotine ‘reward pathways’ in the brain which are thought to play a part in nicotine addiction. It has no contraindications.
Receptor-Ligand Interactions that Generate Proportional Physiological Effects
Published in John C. Matthews, Fundamentals of Receptor, Enzyme, and Transport Kinetics, 2017
We now move up to the next level of complexity and begin to discuss the relationship between fractional receptor occupancy and physiological effect. It is quite possible that a ligand can bind to a receptor and have no physiological effect. Binding alone is not the whole story. Placing a key into a lock alone is generally not sufficient to produce the desired effect, i.e., unlocking the lock and opening the door. You may have several keys on your key ring that will fit into the lock, but probably only one of them is capable of unlocking the lock. Similarly, the ligand must be capable of stimulating the receptor when it binds, such that the receptor can produce its effect. If the binding of a ligand produces receptor stimulation we say that the ligand has intrinsic activity with that receptor, and that the ligand is a receptor agonist. Ligands which bind to a receptor but don’t stimulate it, i.e., those that have zero intrinsic activity, will be discussed in Chapters 7 and 8.
Pharmacological Treatment of Generalised Anxiety Disorder: Current Practice and Future Directions
Published in Expert Review of Neurotherapeutics, 2023
Harry A. Fagan, David S. Baldwin
Neuropeptide Y (NPY) is a 36 amino acid peptide expressed throughout the mammalian brain [110]. Four Y receptors have been identified in humans (Y1, Y2, Y4, and Y5). NPY has been implicated in the stress response, and animal studies suggest differing roles for the different Y receptors. In particular, Y1 receptor stimulation appears to have an anxiolytic effect, while Y2 receptor stimulation may have an anxiogenic effect [110]. The role of NPY has been particularly studied in PTSD, and a recent RCT compared intranasal NPY vs. placebo treatment in patients with this condition [111]. Treatment was generally well tolerated; however, no significant effect was noted on either anxiety scale used, although higher doses were associated with greater improvements in anxiety symptoms [111]. To date, NPY-modulating treatment has not been investigated in clinical populations with GAD. Nor have selective Y receptor agonist/antagonists, which could hold promise in the treatment of anxiety disorders, been investigated in clinical populations.
A mechanistic evaluation of the potential for octamethylcyclotetrasiloxane to produce effects via endocrine modes of action
Published in Critical Reviews in Toxicology, 2021
In order for a chemical to act as a receptor agonist it must be capable of binding in the agonist binding site of its receptor and stimulating (activating) the receptor once bound. Receptor antagonists must be capable of binding to the receptor and interfering with the ability of the receptor to be stimulated by its agonist. Binding between receptors and their agonists or antagonists and the ability of the agonist to stimulate the receptor require that the two molecules “fit” together with very precise interactions. These include high degrees of specificity for size, shape, charge, and chemical properties. Co-activators, co-repressors, agents that interfere with transport or storage of receptor agonists or antagonists, and substances that act to enhance metabolic breakdown of receptor agonists or antagonists, are indirect secondary effects that do not meet the U.S. EPA criteria for evaluation as potential endocrine disruptors.
GLP-1R agonists for the treatment of obesity: a patent review (2015-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Chunxia Liu, Yuxing Zou, Hai Qian
Fc fusion proteins are often homo-dimers, however, hetero-dimers can also be constructed. WO2016077806 discloses a fusion protein comprising two polypeptides, and the peptides which are randomly chosen from a GLP-1 analogue, a glucagon analogue, a GIP analogue or an OXM analogue [107]. The fusion protein provided by WO2020048494 is found for the first time existing in the form of a tetramer, which is more stable than a homodimer Fc fusion protein and effectively prolongs the in vivo half-life [108]. The efficacy obtained from a dual receptor agonist is synergistically improved in comparison to either the native protein agonist or a construct single receptor. WO2018166461, CN110128525, and CN109836486 provide a dual-target fusion protein containing GLP-1 and fibroblast growth factor 21 (FGF21) linked through an immunoglobulin Fc portion, these new compounds have better stability and significantly prolong half-life, and exhibit synergistic effects in reducing blood glucose, lipid, and body weight [109–112].