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      "text": "We see two obvious areas of concern, either or both of which may be responsible: 1) off-target effects related to the H4 receptor, and 2) drug-induced phospholipidosis, a known aspect of pitolisant’s toxicity profile, which we get to in a few slides and which has been swept under the rug.",
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      "text": "Paper on role of histamine receptor H4’s “dominant role in histamine-induced eosinophils adhesion...” In vitro study of histamine and histamine receptor ligands influence on the adhesion of purified human eosinophils to endothelium. Leukocytes adhesion to endothelial cells is one of the most critical event in the inflammatory response. In presented paper using a relevant model of adhesion we have demonstrated that histamine influence eosinophils adhesion to endothelium. This effect appears to be mediated by H4 histamine receptor, while H1, H2 and H3 histamine receptors are not involved.",
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      "text": "Paper on off-target effects of H3 receptor drugs on the H4 receptor. Compared pharmacology of human histamine H3 and H4 receptors: structure–activity relationships of histamine derivatives et al., 2001). The H4R has about 40% sequence homogy to the H3R (58% in transmembrane domains) and both receptors display similar genomic structures with two introns and three exons (Coge et al., 2001b; Tardivel-Lacombe et al., 2001).",
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      "text": "We are troubled at the lack of any mention of eosinophilic abnormality in the FDA’s review documents. We see two obvious areas of concern, either or both of which may be responsible: 1) off-target effects related to the H4 receptor, and 2) drug-induced phospholipidosis, a known aspect of pitolisant’s toxicity profile, which we get to in a few slides and which has been swept under the rug. Pitolisant targets the H3 receptor, which has low sequence homology with the h1 and h2 receptors which limits off-target effects. However, the H3 and H4 receptors have similar homology, which makes it difficult to target the H3 receptor without also impacting the H4 receptor. The H4 receptor plays a key role in inflammatory reactions and “has been show to activate immune cells such as eosinophils.”",
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      "text": "“has been show to activate immune cells such as eosinophils.” — Unattributed",
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      "text": "Source: https://pubmed.ncbi.nlm.nih.gov/26939881/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751501/pdf/147-0706666a.pdf",
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