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Hydrogen sulfide (H₂S) is an endogenous gasotransmitter with anti-inflammatory actions that also reduces itching. To test whether a combination of an antihistamine with a H₂S donor has improved antipruritic efficacy, bifunctional molecules with antihistamine and H₂S-releasing pharmacophores were synthesized and tested in vitro and in vivo. H₂S release from the hybrid molecules was evaluated with the methylene blue and lead acetate methods, and H1-blocking activity was assessed by determining tissue factor expression inhibition. All new compounds released H₂S in a dose-dependent manner and retained histamine blocking activity. Two compounds with the highest potency were evaluated in vivo for their antipruritic as well as sedative action; they proved to possess higher efficacy in inhibiting histamine-induced pruritus and decreased sedative effects compared to the parent compounds (hydroxyzine and …