Effectiveness of histamine receptor antagonists in the treatment of histamine-driven clinical symptoms: do we have a histamine or, better, an anti-histamine problem?

Why are up to 50% of patients with chronic urticaria resistant to antihistamines? Why do many patients with indolent systemic mastocytosis suffer severe symptoms despite treatment with four times the approved antihistamine doses? Do millions of patients with atopic diseases and related disorders have a histamine or, better, an antihistamine problem? If one carefully analyzes human clinical studies with exogenous histamine challenge and endogenous mast cell activation with prophylactic antihistamine pretreatment, the assumed efficacy of antihistamines rapidly fades. Local tissue free drug concentrations of many antihistamines are <100 nM compared with 10-1000 µM possible extracellular local histamine concentrations after mast cell activation. Is the pharmaceutical industry suitably aware of this problem?