AR is a largely heterogenous group of airway diseases, and as such, research should not only focus on immunosuppressive agents (e

AR is a largely heterogenous group of airway diseases, and as such, research should not only focus on immunosuppressive agents (e.g., corticosteroids) but should also include targeted immunomodulatory pathways. focusing on the role of phosphodiesterase-4 (PDE4) inhibitors in AR. PDE4 inhibitors are potent anti-inflammatory agents that are used for the treatment of inflammatory airway diseases including AR. The PDE4 inhibitor roflumilast was shown to effectively control symptoms of AR in a randomized, placebo-controlled, double-blinded, crossover study in patients with a history of AR. However, only a few PDE4 inhibitors have proceeded to phase II and III clinical trials, Rabbit Polyclonal to ZEB2 due to insufficient clinical efficacy and adverse effects. Research is ongoing to develop more effective compounds with fewer side effects that target specific inflammatory pathways in disease pathogenesis Moluccensin V and can provide more consistent benefit to patients with upper airway allergic diseases. Novel specific PDE4 inhibitors seem to fulfill these criteria. are expressed by neutrophils, eosinophils, B cells, T cells, DCs, monocytes, and macrophages. Expression of is typically minimal or absent (Contreras et?al., 2017). Expression is triggered by epithelial damage, microbial invasion, and allergen sensitization. Its inhibition is a?promising target for suppressing inflammatory responses (Contreras et?al., 2017) as was demonstrated for roflumilast in an animal model of acute lung Moluccensin V injury (Kosutova et?al., 2018). PDE4 inhibitors are well-characterized pharmaceutical agents with a broad range of anti-inflammatory activities also in various inflammatory conditions including allergic diseases (Howell et?al., 2018). As aforementioned, PDE4 inhibitors may serve as potential therapeutic agents for various respiratory diseases, as well as for non-Th2 mediated AR. These effects have been evaluated and in animal models of allergic asthma. Their anti-inflammatory activity results from blocking the degradation of cAMP in lymphocytes, eosinophils, neutrophils, and monocytes, leading to the attenuated release of histamine and leukotrienes as well as the release of several cytokines including IL-4, IL-5, IL-10,?and granulocyte-macrophage colony-stimulating factor?(Schmidt et?al., 2001). Inhibition of PDE4 increases accumulation of intracellular cAMP and helps to balance Moluccensin V anti- and pro-inflammatory effects. PDE4 inhibitors such as apremilast, roflumilast, and crisaborole have been tested in clinical trials for various inflammatory diseases. Apremilast is now approved for the treatment of adults with moderate to severe plaque psoriasis and/or psoriatic arthritis (Pincelli et?al., 2018). Roflumilast has shown initial efficacy for treating asthma, COPD, and asthma-COPD overlap (Zhang et?al., 2018). Based on phase III trials, crisaborole is considered an efficacious topical agent with a safety profile and limited systemic exposure. It is promising candidate for the treatment of Moluccensin V atopic dermatitis (Woo and Kuzel, 2019). PDE4 inhibitors, such as roflumilast, are able to suppress various inflammatory responses (Page and Spina, 2011; Urbanova et?al., 2017). A clinical study with oral doses of roflumilast in patients with COPD took place in III trial phases demonstrated its anti-allergic and anti-inflammatory benefits (Page and Spina, 2011). Roflumilast is now approved for treatment of COPD (Heffler et?al., 2019) and is recommended at a dose of 500 g once daily. Many more studies have tested the effects of roflumilast on COPD than on AR (Cilli et?al., 2019). The efficacy and safety profile of roflumilast shows that it leads to more side effects than other PDE4 inhibitors administered intranasally in patients with COPD. The most frequent side effects are nausea, diarrhea, appetite loss and weight loss, abdominal pain, headache, gastrointestinal, and sleep disturbance. These side effects limit the use of roflumilast in clinical practice. Therefore, real-world studies on the clinical use of this PDE4 inhibitor are limited (Cilli et?al., 2019). No effects on the cardiovascular system have been observed (Page and Spina, 2011). The first study to evaluate the efficacy of roflumilast in the treatment of AR was conducted by Schmidt et?al. (2001). In that study, roflumilast was found to be safe and well tolerated at the same dose as that used in COPD, 500 g once a day. Headache was the most common side effect, and was followed by nausea and dizziness in some patients. Three days after the onset of treatment, increased airflow at rhinomanometry was recorded. After 4?d of treatment, subjective improvement of the obstruction was reported by the patients. Taken together, this study provided evidence that orally administered roflumilast is an effective anti-allergy therapy in AR. No further studies have been conducted on the efficacy of roflumilast in AR (Heffler et?al., 2019). Novel PDE4 Inhibitors The clinical development of PDE4 inhibitors has recently Moluccensin V focused on the novel PDE4 inhibitor CHF6001. It has been designed for intranasal delivery which allows CHF6001 to reach therapeutic concentration in the lung.