Phosphodiesterase 4 Inhibitors in Allergic Rhinitis/Rhinosinusitis.

Allergic rhinitis/rhinosinusitis (AR) is the most common allergic disease. It affects patients' quality of life and may influence the severity of lower airway disease such as asthma. Therefore, its treatment is of great importance. AR is treated by a combination of effective approaches; however, in some patients, the disease is uncontrolled. In the last several years, the concept of AR has shifted from increased T helper 2 (Th2) cell signaling and downstream inflammation to disease phenotypes with non-Th2-mediated inflammation. 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. Here, we provide an overview of novel therapies, 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, 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 and can provide more consistent benefit to patients with upper airway allergic diseases. Novel specific PDE4 inhibitors seem to fulfill these criteria.

Clinical considerations when treating neonatal aspiration syndromes.

INTRODUCTION: In physiological conditions, neonatal airways are well-protected against aspiration of fluid or particulate material into the lungs, with laryngeal chemoreflex (LCR) being the most powerful mechanism. Failure of this protection allows substances to enter the lower airways, which starts a series of pathophysiological events initiated by inflammation and surfactant inactivation. The condition is defined as neonatal acute respiratory distress syndrome (ARDS), and its symptoms can range from mild respiratory distress to respiratory failure, often accompanied by persistent pulmonary hypertension (PPHN), in turn even leading to death. The management, therefore, may be very challenging. Areas covered: This review covers protection mechanisms of the neonatal lower airways, the etiology, and pathophysiology of neonatal aspiration syndrome (NAS), its definition in view of current literature, possible treatment options, and future trends. Expert commentary: Inflammation and secondary surfactant deficiency stand in the foreground of neonatal aspiration. Management focuses mainly on appropriate oxygenation, ventilation, improvement in PPHN, and maintenance of systemic circulation, which is largely symptomatic and supportive. Future research is required to evaluate the justification of using exogenous surfactants, antibiotics, anti-inflammatory and antioxidative drugs, or their combinations.

Sensitivity of airway cough-related afferents is influenced by female sex hormones.

Chronic hypersensitivity cough syndrome affects mainly postmenopausal women; however, the pathogenesis of cough hypersensitivity in this demographic is not entirely understood. The role of sex hormones in cough has never been studied in detail; however, sex hormones seem to play an important role in the lung health of women. Our study was aimed to analyse the effect of female sex hormones (oestrogen - E2 and progesterone - Pg) on cough sensitivity measured by inhalation of capsaicin in follicular and luteal phases of menstrual cycle, characterized by significantly different concentrations of sex hormones. These data were compared with a matched group of women taking oral contraceptives. Cough sensitivity to capsaicin increased in luteal phase in subjects with normal menstrual cycle, and this functional change was not present in group with contraceptive pills. The cough sensitivity correlates with the Pg/E2 ratio, and relative lack of oestrogen in luteal phase is associated with higher cough sensitivity to capsaicin.

Modulation of cough response by sensory inputs from the nose - role of trigeminal TRPA1 versus TRPM8 channels.

BACKGROUND: Cough, the most important airways defensive mechanism is modulated by many afferent inputs either from respiratory tussigenic areas, but also by afferent drive from other organs. In animal models, modulation of cough by nasal afferent inputs can either facilitate or inhibit the cough response, depending on the type of trigeminal afferents stimulated. METHODS: In this study we addressed the question of possible bidirectional modulation of cough response in human healthy volunteers by nasal challenges with TRPA1 and TRPM8 agonists respectively. After nasal challenges with isocyanate (AITC), cinnamaldehyde, (-) menthol and (+) menthol (all 10-3 M) nasal symptom score, cough threshold (C2), urge to cough (Cu) and cumulative cough response were measured). RESULTS: Nasal challenges with TRPA1 relevant agonists induced considerable nasal symptoms, significantly enhanced urge to cough (p<0.05) but no statistically significant modulation of the C2 and cumulative cough response. In contrast, both TRPM8 agonists administered to the nose significantly modulated all parameters including C2 (p<0.05), Cu (p<0.01) and cumulative cough response (p <0.01) documenting strong anti irritating potential of menthol isomers. CONCLUSIONS: In addition to trigeminal afferents expressing TRP channels, olfactory nerve endings, trigemino - olfactoric relationships, the smell perception process and other supramedullar influences should be considered as potential modulators of the cough response in humans.