Efficacy and Safety of P. hybridus Leaf Extract Ze 339 for the Treatment of Allergic Rhinitis

Abstract

Allergic rhinitis (AR) is a global health problem on the rise. More and more people are affected, and climate change is exacerbating this health problem in the long term. The quality of life of those affected is often severely compromised, and the financial burden on healthcare systems cannot be disregarded. Therefore, effective and safe medicines are needed to counteract this trend. P. hybridus (butterbur) leaf extract (Ze 339) displays a promising alternative to antihistamines in the treatment of AR symptoms. More than two decades after the first market launch it is now possible to draw a meaningful conclusion on its safety and efficacy. This review summarizes the available preclinical and clinical data, real-world data (RWD) as well as data from post-marketing pharmacovigilance monitoring about the herbal medicinal drug Ze 339. It focusses on the current knowledge about the mode of action as well as the evaluation of its efficacy and safety in the treatment of AR. Given its favourable safety profile and lack of sedative side effects, Ze 339 offers a valuable alternative to antihistamines and should therefore continue to be considered by medical practitioners for the treatment of allergic rhinitis symptoms.

Keywords: Petasites hybridus; Ze 339; allergic rhinitis; butterbur; hay fever; safety.

Figure 1

Structural formulas of sesquiterpene esters neopetasin, petasin and isopetasin.

Figure 2

Schematic overview of the hypothesized mode of action of Ze 339. Ze 339 inhibits the synthesis and release of allergic mediators from allergen-stimulated mast cells and basophils. This relieves both immediate and delayed symptoms associated with inflammation. The figure was created with Biorender.com.

Figure 3

Schematic overview of preclinical data from Ze 339. (1.) Treatment of primary human leukocytes with Ze 339 led to decreased anti-IgE or complement C5a-stimulated LTC4 synthesis. (2.) GM-CSF-priming and complement C5a or PAF stimulation of eosinophils and neutrophils led to the synthesis of cysteinyl LTs and LTB4 which was inhibited by Ze 339. Furthermore, treatment of stimulated eosinophils with petasin reduced the release of ECP. (3.) The treatment with Ze 339 resulted in decreased neutrophil migration towards HNEC supernatant. (4.) Ze 339 inhibited cytokine-induced JAK/STAT signalling. (5.) Treatment of stimulated eosinophils with petasin resulted in reduced intracellular Ca²⁺, reduced cPLA2 activity and reduced 5-LO activity. (6.) Ze 339 application reduced histamine, cysteinyl LTs and LTB4 concentration in nasal fluids of patients. Abbreviations: AA: Arachidonic acid; anti-IgE: anti-immunoglobulin E antibody; complement C5a: complement component 5a; cPLA2: cytosolic phospholipase A2; cysteinyl LTs: cysteinyl leukotrienes; ECP: eosinophil cationic protein; GM-CSF: granulocyte–macrophage colony-stimulating factor; HNEC: human nasal epithelial cells; IL: interleukin; JAK: Janus kinases; LTB4: leukotriene B4; LTC4: leukotriene C4; PAF: platelet activating factor; PL: phospholipids; STAT: signal-transducer and activator of transcription protein; 5-LO: 5-lipoxygenase. The figure was created with Biorender.com.

Figure 4

Overview of efficacy and safety data of Ze 339. List of published randomized controlled trials (RCT) and non-interventional studies (NIS) [30,31,32,33,35,36,37,38]. Abbreviations: AE: adverse event, DDD: defined daily doses. The figure was created with Biorender.com.