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  • The repurposing of well characterized and well

    2022-05-24

    The repurposing of well-characterized and well-tolerated drugs in order to treat illnesses for which they were not originally intended has emerged as an attractive alternative to a long and costly process of drug development. Repositioning antihistaminergic ligands seems a promising idea given that histamine exerts a variety of actions throughout the body and that histamine H1 and H2 receptors are ubiquitously expressed. In this sense, novel clinical applications for histamine H1 receptor antagonists/inverse agonists are currently being studied for the management of different pathological situations, such as inflammatory-related conditions (in combination with glucocorticoids) (Zappia et al., 2015), analgesia (Stein et al., 2016) or neurodegenerative and sleep disorders (Kim and Song, 2017, Krystal, 2015). In the same way, evidence for anti-cancer effects of the histamine H2 receptor inverse agonist cimetidine has been reported in various types of neoplasias, including glioblastoma, cholangiocarcinoma, malignant melanoma, renal cell carcinoma, colorectal and gastric cancer (Dana et al., 2017, Pantziarka et al., 2014). Likewise, histamine H2 receptor antagonist/inverse agonist use was recently associated with a lower risk for incident heart failure and better preserved stroke volume, left ventricular end-diastolic volume, and mass/volume ratio over time in hygromycin dwelling adults (Leary et al., 2016). It would be interesting to determine whether beneficial effects of histamine H2 receptor antagonists/inverse agonists in heart failure pathologies rely, at least partially, on histamine H1 and H2 receptor crossdesensitization/cointernalization. Thus, histamine H2 receptor antagonists/inverse agonists could also modulate the histamine H1 receptor-mediated pro-inflammatory response to endogenous histamine, aiding the resolution of the cardiac disease. We believe that these newly described pharmacological behaviors may encourage and clarify the mechanisms of histamine H2 receptor antagonists/inverse agonists in cardiac tissue. This crosstalk may be responsible for the beneficial effects of histamine H2 receptor inverse agonists on heart pathologies and may also explain unwanted effects of these drugs on other tissues. In this way, Allen et al. reported an anaphylactoid reaction following cessation of high-dose ranitidine in a 19-year-old female with mast cell activation syndrome, hypermobile Ehlers-Danlos syndrome and postural tachycardia syndrome (Allen et al., 2018). The authors suggest that patients who take ranitidine, after withdrawal, can suffer an exacerbated effect of histamine caused by upregulation of histamine H2 receptor and raised histamine levels due to histidine decarboxylase induction, which is in concordance with previous in vitro studies (Alonso et al., 2015, Monczor and Fernandez, 2016, Smit et al., 1996). Considering our present results, it is feasible that in the same way that sustained internalization of histamine H2 receptor led to upregulation on histamine H2 receptor levels, sustained cointernalization of histamine H1 receptor by ranitidine treatment may also lead to upregulation of histamine H1 receptor, which may explain the observed anaphylactoid reaction after cessation of ranitidine treatment. In conclusion, our findings support the notion that the crosstalk between histamine H1 and H2 receptor signaling is not restrictive to agonist ligands and, as a result, may have profound consequences regarding treatment with histamine H1 and H2 receptor antagonists/inverse agonists. Receptor agonists crossregulate receptor inverse agonists response and receptor inverse agonists crossregulate histamine response. Considering the large number of cell types in different tissues that express histamine H1 and H2 receptors, the clinically widespread use of antagonists/inverse agonists acting through both receptors in the treatment of several human diseases, and the advantage of drug repositioning, the accurate characterization of ligands´ mechanisms of action should allow us to reinterpret side effects of drugs and/or to ascribe new uses.