B Cells were exposed for 5 min to increasing concentrations of famotidine and western blot analysis were performed as mentioned above. Data are expressed as times over basal p-ERK levels. AGS cells represent a relevant model concerning H2R histaminergic ligands and their clinical use, and have been extensively used to evaluate histamine action and gastric acid secretion regulation Guo et al. We found that, as well as described for histamine, amthamine and more remarkably famotidine also increased HDC expression, Figure 6B.
Biased signaling of famotidine. Over the past few years, a growing number of articles have been published describing the identification of biased agonists at a wide variety of GPCRs, including several worldwide marketed drugs Kenakin and Miller, ; Bock et al. However, although much has been speculated regarding the potential advantages of this pharmacological feature, and there are several biased agonists entering clinical studies, until now there are no drugs prescribed because of its biased behavior.
In accordance with previous observations made for cimetidine, ranitidine and tiotidine, famotidine-induced H2R desensitization does not involve GRKs participation. Moreover, receptor internalization appeared to mediate receptor down-regulation rather than recycling, opposed to that observed for the agonist amthamine Fernandez et al.
Although ligand efficacies are shared, the involved mechanisms differ, supporting that receptor partners engaged in a certain pathway are strongly dependent on the ligand, adding an additional level of ligand functional selectivity. This phenomenon was also observed for antipsychotic drugs that acting as serotonin antagonists lead to receptor desensitization and internalization Gray and Roth, Webs of potencies and efficacies are a very graphical and informative way of depicting similarities and differences in pharmacological profiles between various ligands Evans et al.
Figure 7 was made collecting data from this work and from bibliography, and represents the relative efficacy in HEKT cells of diverse H2R ligands respect to amthamine.
Web of efficay. Values are percentages relatives to amthamine efficacy for each receptor behavior. The web represents Emax values on a scale from center to exterior line , with intervals of Several decades ago there has been a revolution for the treatment of acid-related disorders.
With the description of the involvement of histamine on gastric acid secretion and the availability of safe antagonists, H2R blockers became of the top marketed drugs around the globe. Various preparations of famotidine are available over the counter in various countries and for decades its use alleviated the symptoms of many people. Till now, accumulated clinical evidence confirms that famotidine is well tolerated and does not have any of the antiandrogenic effects reported with cimetidine. Furthermore, it does not alter the hepatic metabolism of drugs, making of famotidine an effective, well-tolerated and more potent alternative to cimetidine and ranitidine.
In the s, the discovery of proton pumps for controlling gastric acid secretion made of the proton pumps inhibitors the drugs to emerge as the treatment of choice for acid-related diseases. Current guidelines indicate that PPIs should be the first drug treatment, because they are more effective than H2R blockers.
Because of this, H2R blockers almost fell into disuse. Since the recognition of ligand bias, pharmacologists have speculated that using biased ligands could achieve novel pharmacological effects distinct from classical interventions Kenakin, In general, the potential beneficial effects have been emphasized. Biased ligands could surpass on-target adverse events by avoiding undesirable signaling pathways, or increase their efficacy by avoiding or stimulating specific positive or negative feedback loops in signaling pathways.
Numerous examples of each have been proposed. However, here we found a case where ligand bias may drive and be the cause of unwanted side-effects. In our work, we show that famotidine, an H2R inverse agonist whose clinical use lies on the blocking of histamine, actually mimics the effects of the natural agonist concerning G-protein independent signaling pathways.
Prolonged H2R blockade was found to increase parietal cell sensitivity to H2 agonists and tolerance to the treatment. This was explained in terms of receptor upregulation due to structural stabilization of the receptor by the inverse agonists Smit et al.
In this context, the puzzling effect of famotidine over HDC expression could be a supplementary explanation regarding the undesired effects observed after withdrawal of H2R blockers, and may also explain why these ligands produce rebound acid hypersecretion after withdrawal Smith et al.
It can be expected that after famotidine treatment, histamine secretion would be augmented causing a new outbreak of clinical manifestations. The resuming of the treatment should alleviate the symptoms, however, patients are advised not to immediately resume treatment, as rebound symptoms are spontaneously reversible and are likely to improve within a few days. Cumulative knowledge demonstrates that there is a need for the medical community to understand and continue to study biased agonism due to its potential clinical relevance.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Alonso, N. Signal transduction mechanism of biased ligands at histamine H2 receptors. Bakker, R. Histamine receptors: specific ligands, receptor biochemistry, and signal transduction. Allergy Immunol. Black, J. Definition and antagonism of histamine H2 -receptors.
Nature , — Bock, A. Pilot the pulse: controlling the multiplicity of receptor dynamics. Trends Pharmacol. Cappell, M. Clinical presentation, diagnosis, and management of gastroesophageal reflux disease. North Am. Chen, D. Differentiation of the gastric mucosa.
Role of histamine in control of function and integrity of oxyntic mucosa: understanding gastric physiology through disruption of targeted genes. Liver Physiol. Colucci, R. L-histidine decarboxylase decreases its own transcription through downregulation of ERK activity. Davio, C. H1 and H2 histamine receptors in N-nitroso-N-methylurea NMU -induced carcinomas with atypical coupling to signal transducers. Evans, B. Ligand-directed signalling at beta-adrenoceptors. All rights reserved. Information is for End User's use only and may not be sold, redistributed or otherwise used for commercial purposes.
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See more conditions. In some cases your doctor may prescribe an H2 blocker to use 'as required'. This means you only take it when you need it to relieve your symptoms, rather than every day. In some situations you may be prescribed an H2 blocker to be taken every day.
H2 blockers may not be suitable for people with kidney problems or for pregnant or breastfeeding mums. A full list of people who should not take H2 blockers is included with the information leaflet that comes in the medicine packet. If you are prescribed or buy an H2 blocker, read this to be sure you are safe to take it. Note : taking some H2 blockers can affect how well other medicines work. You should also tell your doctor if you take theophylline, a medicine commonly used to treat asthma or chronic obstructive pulmonary disease COPD.
You should consult your doctor if your symptoms worsen, or if you experience any of the following problems which can indicate a serious gut disorder:.
If you are taking antacids you should not take them at the same time as you take your other medication, including H2 blockers. This is because antacids can affect how well other medication is absorbed. If you think you have had a side-effect to one of your medicines you can report this on the Yellow Card Scheme. You can do this online at www. The Yellow Card Scheme is used to make pharmacists, doctors and nurses aware of any new side-effects that medicines or any other healthcare products may have caused.
If you wish to report a side-effect, you will need to provide basic information about:. Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management ; NICE Clinical Guideline Sept - last updated October Br J Gen Pract.
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