Complications Associated with Alloplastic Materials in Rhinoplasty and Their Operative Management.

Whereas rhinoplasty with a reduction of the dorsum and modification of the tip is a common procedure among Caucasians, augmentation of the dorsum remains a challenge in Asians. Choice of the ideal grafting material for dorsal augmentation is a matter of preference and remains under discussion. Autologous and alloplastic materials have their advantages and disadvantages. We report our experiences of the extrusion of alloplastic materials and their management. We report of 18 patients, who had rhinoplasty in the past for dorsal augmentation with alloplastic material. Augmentation rhinoplasty was performed in Asia (n = 15) and Germany (n = 3). All cases showed recurrent signs of foreign body infection and/or partial extrusion and therefore underwent revision surgery in our centers. Once all patients had been successfully treated with antibiotics, we performed a one-stage revision rhinoplasty with explantation of the alloplastic material and subsequent reconstruction with autologous rib cartilage. The nasal dorsum was augmented with either solid rib cartilage grafts, diced cartilage in fascia, or free diced cartilage in platelet-rich fibrin. All patients received pre-, peri-, and postoperative antibiotics. The outcome was screened via clinical examination, ultrasound examination pre- and postoperatively, two-dimensional/three-dimensional (3D) imaging, and magnetic resonance imaging scans.Alloplastic augmentation of the nasal dorsum runs the risk of foreign body reaction, recurrent infections, uncontrolled scarring, and unsatisfying long-term results. We have obtained a series of aesthetically and functionally satisfying results after single-stage revision surgery with autologous cartilage and demonstrate a variety of novel postoperative screening tools including 3D imaging and high-frequency ultrasound. LEVEL OF EVIDENCE: N/A.

Prostaglandin D2 metabolites activate asthmatic patient-derived type 2 innate lymphoid cells and eosinophils via the DP2 receptor.

BACKGROUND: Prostaglandin D2 (PGD2) signaling via prostaglandin D2 receptor 2 (DP2) contributes to atopic and non-atopic asthma. Inhibiting DP2 has shown therapeutic benefit in certain subsets of asthma patients, improving eosinophilic airway inflammation. PGD2 metabolites prolong the inflammatory response in asthmatic patients via DP2 signaling. The role of PGD2 metabolites on eosinophil and ILC2 activity is not fully understood. METHODS: Eosinophils and ILC2s were isolated from peripheral blood of atopic asthmatic patients. Eosinophil shape change, ILC2 migration and IL-5/IL-13 cytokine secretion were measured after stimulation with seven PGD2 metabolites in presence or absence of the selective DP2 antagonist fevipiprant. RESULTS: Selected metabolites induced eosinophil shape change with similar nanomolar potencies except for 9α,11ß-PGF2. Maximal values in forward scatter of eosinophils were comparable between metabolites. ILC2s migrated dose-dependently in the presence of selected metabolites except for 9α,11ß-PGF2 with EC50 values ranging from 17.4 to 91.7 nM. Compared to PGD2, the absolute cell migration was enhanced in the presence of Δ12-PGD2, 15-deoxy-Δ12,14-PGD2, PGJ2, Δ12-PGJ2 and 15-deoxy-Δ12,14-PGJ2. ILC2 cytokine production was dose dependent as well but with an average sixfold reduced potency compared to cell migration (IL-5 range 108.1 to 526.9 nM, IL-13 range: 125.2 to 788.3 nM). Compared to PGD2, the absolute cytokine secretion was reduced in the presence of most metabolites. Fevipiprant dose-dependently inhibited eosinophil shape change, ILC2 migration and ILC2 cytokine secretion with (sub)-nanomolar potencies. CONCLUSION: Prostaglandin D2 metabolites initiate ILC2 migration and IL-5 and IL-13 cytokine secretion in a DP2 dependent manner. Our data indicate that metabolites may be important for in vivo eosinophil activation and ILC2 migration and to a lesser extent for ILC2 cytokine secretion.

The Roles of Type 2 Cytotoxic T Cells in Inflammation, Tissue Remodeling, and Prostaglandin (PG) D2 Production Are Attenuated by PGD2 Receptor 2 Antagonism.

Human type 2 cytotoxic T (Tc2) cells are enriched in severe eosinophilic asthma and can contribute to airway eosinophilia. PGD2 and its receptor PGD2 receptor 2 (DP2) play important roles in Tc2 cell activation, including migration, cytokine production, and survival. In this study, we revealed novel, to our knowledge, functions of the PGD2/DP2 axis in Tc2 cells to induce tissue-remodeling effects and IgE-independent PGD2 autocrine production. PGD2 upregulated the expression of tissue-remodeling genes in Tc2 cells that enhanced the fibroblast proliferation and protein production required for tissue repair and myofibroblast differentiation. PGD2 stimulated Tc2 cells to produce PGD2 using the routine PGD2 synthesis pathway, which also contributed to TCR-dependent PGD2 production in Tc2 cells. Using fevipiprant, a specific DP2 antagonist, we demonstrated that competitive inhibition of DP2 not only completely blocked the cell migration, adhesion, proinflammatory cytokine production, and survival of Tc2 cells triggered by PGD2 but also attenuated the tissue-remodeling effects and autocrine/paracrine PGD2 production in Tc2 induced by PGD2 and other stimulators. These findings further confirmed the anti-inflammatory effect of fevipiprant and provided a better understanding of the role of Tc2 cells in the pathogenesis of asthma.

Preclinical assessment of dual CYP26[A1/B1] inhibitor, DX308, as an improved treatment for keratinization disorders.

Background: Retinoid-based therapies are commonly used in the treatment of disorders of keratinization and other skin disorders but can result in non-specific effects and adverse reactions. Use of retinoic acid metabolism blocking agents (RAMBAs) such as DX308 may address these shortcomings. Objectives: Characterize the therapeutic potential of recently discovered, CYP26-selective RAMBA, DX308. Materials and Methods: Preliminary in vitro assessment of potential off-target activity, metabolic and toxicologic profiling. Studies to assess safety and efficacy of topical treatment in correcting abnormal skin morphology in rhino mice. Extensive gene expression profiling by RNA sequencing and qPCR in 3D epidermis grown with keratinocytes (KCs) from keratinization disorders and healthy controls, to investigate modulation of retinoid biopathways. Results: In vitro, DX308 does not interact with off-target nuclear receptors or CYP450s, is not genotoxic, and is stable in skin, despite vigorous hepatic metabolism. In vivo, topical DX308 induces comedolysis and epidermal thickening without apparent adverse effects. Gene expression profiling shows potent modulation of retinoid-responsive genes by DX308 in both healthy and keratinization disorder KCs. Pathway analysis suggests DX308 may inhibit inflammatory and immune responses in KCs. Conclusions: These preliminary studies suggest that DX308 is an efficacious topical therapeutic with a favourable metabolic and safety profiles. DX308 may present an improved therapeutic alternative for the treatment of keratinization disorders and other retinoid-responsive skin ailments.

[Dorsal preservation septorhinoplasty]. / Die nasenrückenerhaltende "Dorsal-Preservation"-Septorhinoplastik.

BACKGROUND: Nasal dorsum deprojection is a very important tool in functional and aesthetic rhinoplasty. In classic techniques, resection of dorsal bone and cartilage renders dorsal reconstruction necessary. The concept of dorsal preservation rhinoplasty has been known for more than a century but has experienced a renaissance in recent years, with many critical technical modifications. MATERIALS AND METHODS: We present the latest technique of piezo-assisted dorsal preservation rhinoplasty with subdorsal triangular resection and subdorsal Cottle modification based on clinical experience of 205 cases. Furthermore, the advantages and disadvantages of this technique are discussed and several other current variations are presented. RESULTS AND DISCUSSION: Piezo-assisted osteotomy enables a very precise fracture line and sparing of periosteum, with bone sculpting possible even after mobilization. Subdorsal septal height reduction always precedes completion of the osteotomy and nasal bone mobilization, to ensure patient safety with regard to skull base injury. Using the presented technical modifications, the risk of step deformities in the radix is minimized. In selected patients, dorsal preservation septorhinoplasty enables the surgeon to perform very conservative and precise deprojection of the nose with excellent outcomes, although the spectrum of possible complications is shifted in comparison to classic techniques. CONCLUSION: The preliminary experience of 205 cases with a revision rate of less than 10% is promising. A final evaluation of the technique will only be possible after further studies and evaluation of long-term results.

A Study of the Effect of Cyclosporine on Fevipiprant Pharmacokinetics and its Absolute Bioavailability Using an Intravenous Microdose Approach.

This drug-drug interaction study determined the effect of cyclosporine, an inhibitor of organic anion transporting polypeptide (OATP) 1B3 and P-gp, on the pharmacokinetics (PK) of fevipiprant, an oral, highly selective, competitive antagonist of the prostaglandin D2 receptor 2 and a substrate of the two transporters. The concomitant administration of an intravenous microdose of stable isotope-labeled fevipiprant provided the absolute bioavailability of fevipiprant as well as mechanistic insights into its PK and sensitivity to drug interactions. Liquid chromatography-mass spectrometry/mass spectrometry was used to measure plasma and urine concentrations. Geometric mean ratios [90% confidence interval (CI)] for oral fevipiprant with or without cyclosporine were 3.02 (2.38, 3.82) for C max, 2.50 (2.17, 2.88) for AUClast, and 2.35 (1.99, 2.77) for AUCinf The geometric mean ratios (90% CI) for fevipiprant intravenous microdose with or without cyclosporine were 1.04 (0.86, 1.25) for C max, 2.04 (1.83, 2.28) for AUClast, and 1.95 (1.76, 2.16) for AUCinf The absolute bioavailability for fevipiprant was approximately 0.3 to 0.4 in the absence and 0.5 in the presence of cyclosporine. The intravenous microdose allowed differentiation between systemic and presystemic effects of cyclosporine on fevipiprant, demonstrating a small (approximately 1.2-fold) presystemic effect of cyclosporine and a larger (approximately twofold) effect on systemic elimination of fevipiprant. Uptake by OATP1B3 appears to be the rate-limiting step in the hepatic elimination of fevipiprant, whereas P-gp does not have a relevant effect on oral absorption. SIGNIFICANCE STATEMENT: The drug interaction investigated here with cyclosporine, an inhibitor of several drug transporters, provides a refined quantitative understanding of the role of active transport processes in liver and intestine for the absorption and elimination of fevipiprant as well as the basis to assess the need for dose adjustment in the presence of transporter inhibitors. The applied intravenous microdose approach presents a strategy to maximize learnings from a trial, limit the number and duration of clinical trials, and enhance mechanistic drug-drug interaction understanding.

Increased type 2 inflammation post rhinovirus infection in patients with moderate asthma.

Rhinovirus (RV) infections are a major cause of exacerbations in patients with asthma. Experimental RV challenges can provide insight into the pathophysiology of viral exacerbations. Previous reports, investigating mild or moderate asthma patients, have shown an upregulation in type 2 inflammation post RV infection, however, studies specifically involving asthma patients taking inhaled corticosteroids have concentrated on symptoms and lung function, rather than the inflammatory response. Eleven moderate asthma patients were inoculated with RV. Cold symptoms and asthma control were assessed at baseline and post infection. Nasal epithelial lining fluid and bronchial alveolar lavage (BAL) fluid were collected at baseline and 4 days post infection for assessment of inflammatory proteins. Patients suffered increased cold symptoms and decreased asthma control within 7 days of infection. Antiviral mechanisms were induced following inoculation, with increases in interferon -α, ß, γ and λ, as well as CXCL10 and CXCL11. Type 2 inflammatory cytokines were also significantly elevated post RV infection in both nasal and bronchial samples. In BAL, epithelial derived IL-25 and IL-33 levels strongly correlated with Th2 cytokines, IL-4, IL-5 and IL-13. We show how experimental rhinovirus challenge regulates lung and nasal biomarkers in asthma patients taking inhaled corticosteroids. These biomarkers could be used to evaluate the effects of novel drugs for asthma.

Treatment-induced changes of lymphocyte subsets in patients with adenoid cystic carcinoma of the head and neck.

PURPOSE: Adenoid cystic carcinoma (ACC) of the head and neck is a rare and highly malignant tumor, characterized by perineural growth and early distant metastases. The composition of immune cells in the peripheral blood and the tumor microenvironment is critical to tumor growth and control. However, little is known about the frequency and function of the relevant immune cell subsets in this entity. METHODS: In ACC patients (n = 11) and matched healthy donors (n = 11), the frequency of peripheral blood T and B cells was measured by flow cytometry at different treatment stages of disease (24 samples). Cells were further characterized by their expression of CCR7, PD-1, CD39 and CD73. Tumor-infiltrating lymphocytes (TIL) were analyzed by immunohistochemistry for ten patients and for three patients by flow cytometry. RESULTS: CD4+ T cells had significantly lower frequency after radiotherapy (RT). All other cell frequencies, including Treg, were stable through course of the disease. In B cells, CD73 was reduced after RT. CCR7 expression on T and B cells in patients with relapse/metastases (R/M) differed significantly from patients with active disease. PD-1 remained stable. Treg were more present in TIL compared to peripheral blood. CONCLUSION: Composition of lymphocyte subgroups behaves similar to squamous cell carcinoma in the head and neck, except for Treg, which remained stable. Nevertheless, the CD4+/Treg ratio was lower after RT, which could stand for an immunosuppressive effect in these patients. Therefore, it could be beneficial treating ACC with combined RT and immunomodulatory drugs.

Omalizumab normalizes the gene expression signature of lesional skin in patients with chronic spontaneous urticaria: A randomized, double-blind, placebo-controlled study.

BACKGROUND: Omalizumab, a humanized recombinant monoclonal anti-IgE antibody, proved to be effective in patients with chronic spontaneous urticaria (CSU), including severe and treatment-refractory CSU. Here, we report omalizumab's effect on gene expression in skin biopsies from CSU patients enrolled in a double-blind, placebo-controlled study. METHODS: Chronic spontaneous urticaria patients (18-75 years) were randomized to either 300 mg omalizumab (n = 20) or placebo (n = 10) administered s.c. every 4 weeks for 12 weeks (NCT01599637). Lesional and nonlesional skin biopsies were collected from the same area of consenting patients and assessed at baseline and on Day 85 compared with skin biopsies from the same area of 10 untreated healthy volunteers (HVs). Gene expression data were generated using Affymetrix HG-U133Plus2.0 microarrays. Statistical analyses were performed using R packages. RESULTS: At baseline, 63 transcripts were differentially expressed between lesional and nonlesional skin. Two-thirds of these lesional signatures were also differentially expressed between lesional and HV skin. Upon treatment with omalizumab, >75% of lesional signatures changed to reflect nonlesional skin expression levels (different vs placebo, P < 0.01). Transcripts upregulated in lesional skin (vs nonlesional and/or HV skin) suggested increased mast cell/leukocyte infiltration (FCER1G, C3AR1, CD93, S100A8, and S100A9), increased oxidative stress, vascularization (CYR61), and skin repair events (KRT6A, KRT16). Lesional signatures were not modulated by treatment in nonresponders (defined based on UAS7 longitudinal changes ≥16). CONCLUSION: Omalizumab, in treatment responders, reverted transcriptional signatures associated with CSU lesion phenotype to reflect nonlesional/HV expression levels; this is consistent with observed omalizumab-mediated clinical improvement observed in patients with CSU.

The prostaglandin D2 receptor 2 pathway in asthma: a key player in airway inflammation.

Asthma is characterised by chronic airway inflammation, airway obstruction and hyper-responsiveness. The inflammatory cascade in asthma comprises a complex interplay of genetic factors, the airway epithelium, and dysregulation of the immune response.Prostaglandin D2 (PGD2) is a lipid mediator, predominantly released from mast cells, but also by other immune cells such as TH2 cells and dendritic cells, which plays a significant role in the pathophysiology of asthma. PGD2 mainly exerts its biological functions via two G-protein-coupled receptors, the PGD2 receptor 1 (DP1) and 2 (DP2). The DP2 receptor is mainly expressed by the key cells involved in type 2 immune responses, including TH2 cells, type 2 innate lymphoid cells and eosinophils. The DP2 receptor pathway is a novel and important therapeutic target for asthma, because increased PGD2 production induces significant inflammatory cell chemotaxis and degranulation via its interaction with the DP2 receptor. This interaction has serious consequences in the pulmonary milieu, including the release of pro-inflammatory cytokines and harmful cationic proteases, leading to tissue remodelling, mucus production, structural damage, and compromised lung function. This review will discuss the importance of the DP2 receptor pathway and the current understanding of its role in asthma.

U-BIOPRED: evaluation of the value of a public-private partnership to industry.

Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) was initiated in the first year of the Innovative Medicines Initiative (IMI). It was an ambitious plan to tackle the understanding of asthma through an integration of clinical and multi-'omics approaches that necessitated the bringing together of industry, academic, and patient representatives because it was too large to be managed by any one of the partners in isolation. It was a novel experience for all concerned. In this review, we describe the main features of the U-BIOPRED experience from the industry perspective. We list some of the key advantages and learnings from the perspective of the authors, and also improvements that we feel could be made in future projects.

Influence of physical activity on addiction parameters of rats exposed to amphetamine which were previously supplemented with hydrogenated vegetable fat.

Amphetamine (AMPH) and its derivatives are addictive drugs used to promote and enhance alertness, motivation, willingness, courage and wellbeing. However, their chronic use is related to memory loss, emotional instability, insomnia, psychosis and paranoia. In the last decades, modern society has included processed foods, rich in trans fatty acids (TFA), in their diet, what has been related to several health problems including increased AMPH preference and self-administration. In this scenario, physical activity appears to be useful to attenuate rewarding symptoms related to addictive drugs mainly by affecting brain neuroplasticity and neurotransmission. The current study has been developed to assess the influence of physical activity on addiction parameters of rats exposed to AMPH which were previously supplemented with hydrogenated vegetable fat (HVF), rich in TFA. After six weeks of HVF or soybean oil (SO, control group) supplementation, adult rats were conditioned with d,l-AMPH or vehicle for 14 days. Then, half of each experimental group was submitted to physical activity in treadmill running sessions (60min/day, 5 days/week) for 5 weeks. Animals were re-conditioned with AMPH or vehicle for 3 more days, to observe drug relapse. Locomotor activity and anxiety-like symptoms were observed 24h after the last AMPH reconditioning, and fatty acids composition was quantified in the ventral tegmental area, striatum and prefrontal cortex. All animals showed AMPH preference, but only SO sedentary showed drug relapse. No differences were observed in locomotor activity among groups, while HVF-supplemented group showed decreased exploration per se, and physical activity prevented this. Moreover, AMPH-HVF group showed increased anxiety-like symptoms, which were prevented by physical activity. These results indicate that HVF supplementation modifies AMPH addiction, whereas regular physical activity could be protective against both AMPH and TFA damages.

Treatment of ear keloids: algorithm for a multimodal therapy regimen.

Keloids are benign cutaneous lesions, arising from proliferating fibroblasts. Keloids of the ear may occur after trauma, surgery or helix piercings and are difficult to treat, since they tend to form recurrences. Guidelines suggest multimodal therapy; however, recurrence rates remain high and distinct algorithms for the combination of different modalities are missing. To unravel the most effective combination of therapeutic options for keloids of the ear, 38 patients with the diagnosis of an ear keloid were included in our cohort. In a prospective subgroup (B) of this cohort (n = 17), patients either underwent surgery using the "fillet technique" (a meticulous peeling of the keloid skin) and intra-lesional injections of triamcinolone 10 mg/ml every 4-6 weeks for 6 months, or they were additionally treated with a non-customized pressure device which was recommended for at least 16/24 h per day over 6 months. To further compare our results, the remaining 21 patients of our cohort, who were treated at our clinic before, were retrospectively evaluated concerning their recurrence rates. The mean follow-up was 48 months. The mean count of adjuvant steroid injections was two in all patients, four in subgroup B. The recurrence rate was 30% (13/38) in all patients (subgroup B 0/17). Aesthetic results were good to excellent in all non-recurrent cases. No patient treated with fillet technique showed recurrence (p < 0.001). However, we could not confirm a significant effect but a trend of repeated steroid injections for preventing recurrences (p = 0.099). The application of pressure using our non-customized clip also showed a clear trend towards preventing recurrences in cross-table analysis (p = 0.057). Although several studies on different treatment regimens for keloids of the ear exist, the effectiveness of a multimodal treatment regimen needs to be elucidated. Overall, the best results in preventing recurrences were achieved by combining three different treatments. However, the fillet technique was the only modality preventing recurrences of keloids in uni- and multivariate analysis. The application of pressure with a non-customized clip and repeated steroid injections also showed a positive trend but failed level of significance. Based on our data and the literature we recommend, when feasible, the combination of more than one therapeutic regimen, since relapse risk went down from single to dual and triple therapy from 40% (8/20) to 14.3% (2/14) to 0% (0/4), respectively in our cohort. The use of "fillet technique" was especially beneficial.

Synchronous bilateral tonsil carcinoma: case presentation and review of the literature.

BACKGROUND: The incidence of synchronous bilateral tonsil carcinoma seems to be underreported. For adequate oncologic treatment, it is mandatory to remove all primaries to prevent recurrence or metachronic disease. The purpose of this manuscript is to provide a comprehensive review on this topic and to emphasize the need of bilateral tonsillectomy in cases of cancer of unknown primary (CUP) as well as in the case of a unilateral tonsillar carcinoma. MATERIAL AND METHODS: A systematic review of the literature was performed for "bilateral tonsillar neoplasm", "synchronous cancer of the oropharynx" and "cancer of unknown primary in head and neck". RESULTS: We present a clinical case with bilateral tonsillar carcinoma in initially suggested cancer of unknown primary. Clinically, both tonsillar sites were unsuspicious, but in PET/CT an ipsilateral enhancement of the tonsil area was detected. The pathological work up of bilateral tonsillectomy specimens revealed bilateral squamous cell carcinoma with HPV-type 16 positivity. The review of the literature revealed 29 cases of bilateral tonsil cancer. CONCLUSION: The handling of tonsillar tissue in the frame of panendoscopy in the case of CUP is still controversial. We recommend a bilateral tonsillectomy as a routine procedure for cancer of unknown primary as well as unilateral tonsillar carcinoma. Herewith the detrimental consequences of occult metachronous contralateral tonsillar carcinoma can be prevented.

[The 8th edition of the AJCC Cancer Staging Manual : Updates in otorhinolaryngology, head and neck surgery]. / Die 8. Ausgabe der TNM­Klassifikation : Neuerungen für das Fachgebiet Hals­Nasen­Ohren­Heilkunde, Kopf- und Halschirurgie.

BACKGROUND: The TNM system is an established tool for classification of solid tumors by means of tumor size and extent, the involvement of local lymph nodes, and the presence of distant metastases. The classification was established in order to visualize prognostic implications and to allow establishment of systematic therapeutic algorithms. Since the beginning of 2017 a revised version of the classification has applied. Particularly the classification of otorhinolaryngologic tumors has been thoroughly revised in the 8th edition, partly on the basis of new prognostically relevant parameters, such as infection with oncogenic human papillomavirus (HPV) subtypes. MATERIALS AND METHODS: The 8th edition of the American Joint Committee on Cancer (AJCC) served as a basis for the review. The highlighted changes were supplemented by a literature review and the most important elements were summarized. RESULTS: Substantial changes were made for oropharyngeal carcinomas caused by HPV, for the classification of lymph node metastases under consideration of extranodal extension, and for classification of tumors of the oral cavity. Due to their frequency and special biology, skin tumors in the head and neck area are now described in a separate chapter. CONCLUSION: The new classification is a challenge for all specialties involved in tumor staging and therapy. The advantage for the patient lies in a more accurately adjustable treatment modality through more precise classification of tumors. Good collaboration and rapid implementation of the new classification is required in all disciplines involved in head neck tumor diagnostics and therapy.

Clinical efficacy of omalizumab in chronic spontaneous urticaria is associated with a reduction of FcεRI-positive cells in the skin.

Background. Treatment with omalizumab, a humanized recombinant monoclonal anti-IgE antibody, results in clinical efficacy in patients with Chronic Spontaneous Urticaria (CSU). The mechanism of action of omalizumab in CSU has not been elucidated in detail. Objectives. To determine the effects of omalizumab on levels of high affinity IgE receptor-positive (FcεRI+) and IgE-positive (IgE+) dermal cells and blood basophils. Treatment efficacy and safety were also assessed. Study design. In a double-blind study, CSU patients aged 18­75 years were randomized to receive 300 mg omalizumab (n=20) or placebo (n=10) subcutaneously every 4 weeks for 12 weeks. Changes in disease activity were assessed by use of the weekly Urticaria Activity Score (UAS7). Circulating IgE levels, basophil numbers and levels of expression of FcεRI+ and IgE+ cells in the skin and in blood basophils were determined. Results. Patients receiving omalizumab showed a significantly greater decrease in UAS7 compared with patients receiving placebo. At Week 12 the mean difference in UAS7 between treatment groups was -14.82 (p=0.0027), consistent with previous studies. Total IgE levels in serum were increased after omalizumab treatment and remained elevated up to Week 12. Free IgE levels decreased after omalizumab treatment. Mean levels of FcεRI+ skin cells in patients treated with omalizumab 300 mg were decreased at Week 12 compared with baseline in the dermis of both non-lesional and lesional skin, reaching levels comparable with those seen in healthy volunteers (HVs). There were no statistically significant changes in mean FcɛRI+ cell levels in the placebo group. Similar results were seen for changes in IgE+ cells, although the changes were not statistically significant. The level of peripheral blood basophils increased immediately after treatment start and returned to Baseline values after the follow-up period. The levels of FcεRI and IgE expression on peripheral blood basophils were rapidly reduced by omalizumab treatment up to Week 12. Conclusions. Treatment with omalizumab resulted in rapid clinical benefits in patients with CSU. Treatment with omalizumab was associated with reduction in FcɛRI+ and IgE+ basophils and intradermal cells.

Absorption, Distribution, Metabolism, and Excretion of the Oral Prostaglandin D2 Receptor 2 Antagonist Fevipiprant (QAW039) in Healthy Volunteers and In Vitro.

Fevipiprant is a novel oral prostaglandin D2 receptor 2 (DP2; also known as CRTh2) antagonist, which is currently in development for the treatment of severe asthma and atopic dermatitis. We investigated the absorption, distribution, metabolism, and excretion properties of fevipiprant in healthy subjects after a single 200-mg oral dose of [14C]-radiolabeled fevipiprant. Fevipiprant and metabolites were analyzed by liquid chromatography coupled to tandem mass spectrometry and radioactivity measurements, and mechanistic in vitro studies were performed to investigate clearance pathways and covalent plasma protein binding. Biotransformation of fevipiprant involved predominantly an inactive acyl glucuronide (AG) metabolite, which was detected in plasma and excreta, representing 28% of excreted drug-related material. The AG metabolite was found to covalently bind to human plasma proteins, likely albumin; however, in vitro covalent binding to liver protein was negligible. Excretion was predominantly as unchanged fevipiprant in urine and feces, indicating clearance by renal and possibly biliary excretion. Fevipiprant was found to be a substrate of transporters organic anion transporter 3 (OAT3; renal uptake), multidrug resistance gene 1 (MDR1; possible biliary excretion), and organic anion-transporting polypeptide 1B3 (OATP1B3; hepatic uptake). Elimination of fevipiprant occurs via glucuronidation by several uridine 5'-diphospho glucuronosyltransferase (UGT) enzymes as well as direct excretion. These parallel elimination pathways result in a low risk of major drug-drug interactions or pharmacogenetic/ethnic variability for this compound.