Assessment of Biomarker Heterogeneity in Sinus Versus Inferior Turbinate Tissue in Patients Without Chronic Rhinosinusitis.

BACKGROUND: Currently, no consensus exists on the appropriate control specimen site to utilize in studies evaluating for biomarkers in chronic rhinosinusitis (CRS). Studies thus far have utilized tissue from various anatomic sites despite regional heterogeneity. OBJECTIVE: We set out to quantify the differences in biomarker levels present in inferior turbinate versus sphenoid sinus mucosa in paired healthy control patients. We hypothesize that statistically significant differences in cytokine/chemokine expression exist between these two distinct sites. METHODS: A 38-plex commercially available cytokine/chemokine Luminex Assay was performed on 54 specimens encompassing paired inferior turbinate and sphenoid sinus mucosa samples from 27 patients undergoing endoscopic anterior skull base surgery. Patients with a history of CRS were excluded. Paired sample t-tests and Fisher's exact tests were performed. RESULTS: Twenty-seven patients were included in the study, including 10 male and 17 female patients with an average age of 48 years. The following 8 biomarkers had statistically significant concentration differences between inferior turbinate mucosa and sphenoid mucosa sites: Flt-3L, Fractalkine, IL-12p40, IL-1Ra, IP-10, MCP-1, MIP-1ß, and VEGF, with all P-values <0.01. CONCLUSION: No consensus exists regarding the optimal choice of control specimen for CRS research. We present statistically significant quantitative differences in biomarker levels between paired inferior turbinate and sphenoid mucosa samples. This confirms the presence of heterogeneity between different subsites of sinonasal mucosa and highlights the need for standardization in future CRS research.

Evaluation of both exonic and intronic variants for effects on RNA splicing allows for accurate assessment of the effectiveness of precision therapies.

Elucidating the functional consequence of molecular defects underlying genetic diseases enables appropriate design of therapeutic options. Treatment of cystic fibrosis (CF) is an exemplar of this paradigm as the development of CFTR modulator therapies has allowed for targeted and effective treatment of individuals harboring specific genetic variants. However, the mechanism of these drugs limits effectiveness to particular classes of variants that allow production of CFTR protein. Thus, assessment of the molecular mechanism of individual variants is imperative for proper assignment of these precision therapies. This is particularly important when considering variants that affect pre-mRNA splicing, thus limiting success of the existing protein-targeted therapies. Variants affecting splicing can occur throughout exons and introns and the complexity of the process of splicing lends itself to a variety of outcomes, both at the RNA and protein levels, further complicating assessment of disease liability and modulator response. To investigate the scope of this challenge, we evaluated splicing and downstream effects of 52 naturally occurring CFTR variants (exonic = 15, intronic = 37). Expression of constructs containing select CFTR intronic sequences and complete CFTR exonic sequences in cell line models allowed for assessment of RNA and protein-level effects on an allele by allele basis. Characterization of primary nasal epithelial cells obtained from individuals harboring splice variants corroborated in vitro data. Notably, we identified exonic variants that result in complete missplicing and thus a lack of modulator response (e.g. c.2908G>A, c.523A>G), as well as intronic variants that respond to modulators due to the presence of residual normally spliced transcript (e.g. c.4242+2T>C, c.3717+40A>G). Overall, our data reveals diverse molecular outcomes amongst both exonic and intronic variants emphasizing the need to delineate RNA, protein, and functional effects of each variant in order to accurately assign precision therapies.

Assessment of the effectiveness of platelet rich fibrin in the treatment of Schneiderian membrane perforation.

BACKGROUND: The objective of this study is to evaluate the effect of Platelet rich fibrin (PRF) treatment of maxillary sinus membrane perforation on bone formation and new vascular supply and the success of dental implant survival rate. METHODS: The dataset for this retrospective study consists of patients who received sinus augmentation using the lateral wall technique. A total of 16 patients (20 sinuses) the patients without sinus membrane perforation (10 maxiller sinus area with sinus floor augmentation) and with Schneiderian perforation (10 maxiller sinus area repairing with PRF and augmented sinus floor area) were included in this study. The bone height was measured by comparing the preoperative and postoperative dental CBCT scans. Histological sections were evaluated for possible vasculogenesis augmented sinuses area. RESULTS: In both groups, it was observed that the possible vasculogenesis augmented sinuses area increased. Implant survival rates in both groups found that one hundred percent and any bone loss around implants were not observed. An apparent increase in alveolar bone height was observed and measured in CBCT scans. CONCLUSIONS: PRF can be considered as an alternative material for repairing sinus perforations because it is fully autogenous and easy manipulated.

Evaluation of the Tobacco Heating System 2.2. Part 7: Systems toxicological assessment of a mentholated version revealed reduced cellular and molecular exposure effects compared with mentholated and non-mentholated cigarette smoke.

Modified risk tobacco products (MRTPs) are being developed with the aim of reducing smoking-related health risks. The Tobacco Heating System 2.2 (THS2.2) is a candidate MRTP that uses the heat-not-burn principle. Here, systems toxicology approaches were engaged to assess the respiratory effects of mentholated THS2.2 (THS2.2M) in a 90-day rat inhalation study (OECD test guideline 413). The standard endpoints were complemented by transcriptomics and quantitative proteomics analyses of respiratory nasal epithelium and lung tissue and by lipidomics analysis of lung tissue. The adaptive response of the respiratory nasal epithelium to conventional cigarette smoke (CS) included squamous cell metaplasia and an inflammatory response, with high correspondence between the molecular and histopathological results. In contrast to CS exposure, the adaptive tissue and molecular changes to THS2.2M aerosol exposure were much weaker and were limited mostly to the highest THS2.2M concentration in female rats. In the lung, CS exposure induced an inflammatory response, triggered cellular stress responses, and affected sphingolipid metabolism. These responses were not observed or were much lower after THS2.2M aerosol exposure. Overall, this system toxicology analysis complements and reconfirms the results from classical toxicological endpoints and further suggests potentially reduced health risks of THS2.2M.

Ufasomes nano-vesicles-based lyophilized platforms for intranasal delivery of cinnarizine: preparation, optimization, ex-vivo histopathological safety assessment and mucosal confocal imaging.

To circumvent the low and erratic absorption of orally administrated cinnarizine (CN), intranasal lyophilized gels containing unsaturated fatty acid liposomes (ufasomes) and encapsulating CN were prepared from oleic acid using a simple assembling strategy. The effects of varying drug concentration and cholesterol percentage on ufasomes size, polydispersity index and entrapment efficiency were investigated using 3(1)4(1) full factorial design. The optimized ufasomes that contained 14% cholesterol relative to oleic acid displayed spherical morphology with average size of 788 nm and entrapment efficiency of 80.49%. To overcome the colloidal instability of CN-loaded ufasomes dispersions and their short residence time in the nasal cavity, the ufasomes were incorporated into mucoadhesive hydrogels that were lyophilized into unit dosage forms for accurate dosing. Scanning electron micrographs of the lyophilized gel revealed that the included ufasomes were intact, non-aggregating and maintained their spherical morphology. Rheological characterization of reconstituted ufasomal lyophilized gel ensured ease of application. Furthermore, the gel induced minor histopathological alterations in sheeps' nasal mucosa. Ex-vivo confocal laser imaging confirmed the ability of ufasomes to penetrate deep through nasal mucosa layers. The results highlighted in the current work confirm the feasibility of using CN-loaded ufasomal gels for intranasal drug delivery.

Assessment of mucosal changes associated with nasal splint in a rabbit model / Avaliação sobre alterações na mucosa, associadas ao uso de splints nasais, utilizando coelhos como cobaias

INTRODUCTION: There is no consensus on duration of the nasal splint after nasal septum surgeries. The pressure of nasal splint on the mucosa may cause tissue necrosis and nasal septum perforation. OBJECTIVES: To investigate the histopathological changes of the nasal mucosa caused by nasal splints in a rabbit model. METHODS: No splint was used in group A. Bilateral silicone nasal splints were placed for five, ten, and 15 days in groups B, C, and D, respectively. Biopsy of the nasal mucosa was performed after removal of splint. Histopathologic evaluations were performed. The severity and depth of the inflammation were scored. RESULTS: Group A had a normal histological appearance. Comparison of the results of groups B, C, and D with group A demonstrated statistically significant differences with regards to the severity of histopathological findings. There was no statistically significant difference between groups B and C. There were statistically significant differences between the groups B and D, and also between groups C and D. CONCLUSIONS: Longer duration of nasal splint had a higher risk for septal perforation. Therefore, removal of the splint as soon as possible may be helpful for preventing potential perforations. .

INTRODUÇÃO: Não existe consenso acerca do tempo de permanência de splints nasais no pós-operatório de cirurgias no septo. A pressão causada pelos mesmos na mucosa nasal pode causar necrose e perfurações septais. OBJETIVOS: Investigar mudanças histopatológicas da mucosa nasal causadas por splints nasais em coelhos. MÉTODO: Nenhum splint foi utilizado no grupo A. Splints de silicone foram utilizados por 5, 10 e 15 dias nos grupos B, C e D, respectivamente. Biópsia da mucosa nasal foi realizada após a remoção dos mesmos. Avaliações histopatológicas foram realizadas, e a gravidade e a profundidade do processo inflamatório foram medidas. RESULTADOS: Grupo A apresentou uma aparência histológica normal. Comparações de resultados entre os grupos B, C e D com o grupo A demonstraram diferenças estatísticas relevantes na gravidade histopatológica. Não houve diferenças estatísticas relevantes entre os grupos B e D, assim como entre os grupos C e D. CONCLUSÃO: De acordo com os resultados, quanto maior a duração no uso de splints nasais maior o risco de perfuração septal. Portanto, a remoção de splints nasais deve ser realizada assim que possível, prevenindo potenciais perfurações. .

Impact assessment of repeated exposure of organotypic 3D bronchial and nasal tissue culture models to whole cigarette smoke.

Cigarette smoke (CS) has a major impact on lung biology and may result in the development of lung diseases such as chronic obstructive pulmonary disease or lung cancer. To understand the underlying mechanisms of disease development, it would be important to examine the impact of CS exposure directly on lung tissues. However, this approach is difficult to implement in epidemiological studies because lung tissue sampling is complex and invasive. Alternatively, tissue culture models can facilitate the assessment of exposure impacts on the lung tissue. Submerged 2D cell cultures, such as normal human bronchial epithelial (NHBE) cell cultures, have traditionally been used for this purpose. However, they cannot be exposed directly to smoke in a similar manner to the in vivo exposure situation. Recently developed 3D tissue culture models better reflect the in vivo situation because they can be cultured at the air-liquid interface (ALI). Their basal sides are immersed in the culture medium; whereas, their apical sides are exposed to air. Moreover, organotypic tissue cultures that contain different type of cells, better represent the physiology of the tissue in vivo. In this work, the utilization of an in vitro exposure system to expose human organotypic bronchial and nasal tissue models to mainstream CS is demonstrated. Ciliary beating frequency and the activity of cytochrome P450s (CYP) 1A1/1B1 were measured to assess functional impacts of CS on the tissues. Furthermore, to examine CS-induced alterations at the molecular level, gene expression profiles were generated from the tissues following exposure. A slight increase in CYP1A1/1B1 activity was observed in CS-exposed tissues compared with air-exposed tissues. A network-and transcriptomics-based systems biology approach was sufficiently robust to demonstrate CS-induced alterations of xenobiotic metabolism that were similar to those observed in the bronchial and nasal epithelial cells obtained from smokers.

Cytological assessment of the epithelial cells of the nasal mucous membrane after local fluticasone therapy.

The majority of cytological studies concern the influence of glucocorticosteroids on cells involved in creating and sustaining inflammation, such as eosinophils or neutrophils. Much less attention is devoted to epithelial cells. It should also be noticed that glucocorticosteroid drugs administered nasally for local action can significantly change the cytological image of the nasal mucous membrane. Therefore, the purpose of this research was to cytologically assess the influence of topical fluticasone therapy on the nasal mucous membrane cells, with special attention for the changes in the morphology of epithelial cells. The research samples were taken from patients with symptoms of chronic rhinitis and suspected allergies. The research was a two-step process. In the first step, a smear was taken from the surface of the nasal mucous membrane of the above-mentioned patients before the start of therapy and the obtained cytological image was compared with a control image of the nasal mucous of healthy people. Step two involved the cytology of the same patients after 4 weeks of fluticasone therapy, applied as a nasal aerosol in two doses of 50 µg to each nostril once per day, in the combined daily dose of 200 µg (for adults and children aged 12 or more). Children aged between 4 and 12 were given a single dose of 50 µg to each nostril once per day, in a daily dose of 100 µg. Based on smears stained according to the Papanicolaou and Pappenheim method, a qualitative and quantitative analysis of changes in the mucous membrane of nasal cells was performed. The cytological assessment of nasal mucous membrane stains of patients with chronic rhinitis before fluticasone treatment enabled a diagnosis of chronic infectious rhinitis, compared through the presence of numerous neutrophils and bacteria. The studied samples did not show significant changes in the morphology of epithelial cells, only a few cells with mild vacuolation changes of the cytoplasm were found. The use of fluticasone, however, caused a significant decrease in the neutrophilia and the appearance of numerous epithelial cells with intensified cytoplasm vacuolation in the sample. The results obtained allow us to conclude that standard fluticasone therapy as administered nasally in aerosol form to patients with diagnosed nonallergic nasal mucous membrane inflammation caused a significant reduction in the inflammation without showing cytological characteristics of damage to the epithelium of the nasal mucous membrane. The intensified vacuolation observed in the cytoplasm of epithelial cells, most prominently in the columnar cells, might suggest the stimulation of autophagic processes.

Assessment of mucosal changes associated with nasal splint in a rabbit model.

INTRODUCTION: There is no consensus on duration of the nasal splint after nasal septum surgeries. The pressure of nasal splint on the mucosa may cause tissue necrosis and nasal septum perforation. OBJECTIVES: To investigate the histopathological changes of the nasal mucosa caused by nasal splints in a rabbit model. METHODS: No splint was used in group A. Bilateral silicone nasal splints were placed for five, ten, and 15 days in groups B, C, and D, respectively. Biopsy of the nasal mucosa was performed after removal of splint. Histopathologic evaluations were performed. The severity and depth of the inflammation were scored. RESULTS: Group A had a normal histological appearance. Comparison of the results of groups B, C, and D with group A demonstrated statistically significant differences with regards to the severity of histopathological findings. There was no statistically significant difference between groups B and C. There were statistically significant differences between the groups B and D, and also between groups C and D. CONCLUSIONS: Longer duration of nasal splint had a higher risk for septal perforation. Therefore, removal of the splint as soon as possible may be helpful for preventing potential perforations.

A 26-Week Toxicity Assessment of AIR001 (Sodium Nitrite) by Inhalation Exposure in Rats and by Intravenous Administration in Dogs.

Historically, nitrogen oxides (NOx) in food, drinking water, as well as in the atmosphere have been believed to be associated with adverse health consequences. More recently, NOx have been implicated in normal homeostatic regulation, and exogenous administration has been associated with health benefits. One such potential health benefit is the prospect that inhaled nitrite will lower pulmonary blood pressure (BP) in patients with pulmonary arterial hypertension (PAH), a disease with poor prognosis due to the lack of effective treatment. To characterize potential chronic toxicity associated with inhaled AIR001 (sodium nitrite) for use in the treatment of PAH, 26-week exposures to AIR001 were carried out by inhalation administration in rats and by intravenous infusion in dogs. The studies revealed that methemoglobinemia was the primary adverse effect in both species. Methemoglobin levels less than 40% were well tolerated in both species, while levels greater than 50% methemoglobin caused death in some rats. Additionally, a decrease in systemic BP was also observed with inhaled AIR001 exposure in dogs. These acute secondary and exaggerated pharmacological effects occurred daily throughout the 26-week treatment period. Chronic exposure did not alter the magnitude of either methemoglobinemia or hypotension or result in additional toxicity or compensatory responses. Based on the exposure levels that produced these pharmacodynamic responses in animals, relative to those measured in early clinical studies, it appears that an adequate margin of safety exists to support the continued clinical development of inhaled AIR001.

Nasal cytological assessment after crenotherapy in the treatment of chronic rhinosinusitis in the elderly.

Chronic rhinosinusitis (CRS) determines irreversible alterations of the nasal mucosa with consequent impairment of ciliary movements and, therefore, mucociliary clearance (MCC). People of all ages can be affected by CRS but the elderly are subjects at the highest risk. CRS in the elderly with an age-related physiological impairment of nasal respiratory function, often accompanied by other chronic diseases, requires additional therapies to be added to the numerous daily medications. Since the currently available therapies for CRS include the use of drugs that can have adverse effects and contraindications, crenotherapy could represent a therapeutic option. Indeed, because the adverse effects and contraindications of crenotherapy are scarce, it can be safely used in elderly patients with comorbidities. The aim of this study is to evaluate the nasal cytological assessment after crenotherapy in elderly subjects with CRS. Two groups, comprising a total of 84 elderly subjects with CRS, were treated with crenotherapy with sodium chloride sulphate hyperthermal water rich in mineral salts (group I, n=49) and saline solution (group II n=35). Cytological assessment for both groups took place at baseline (T0) and 1 month after treatment (T30). At T30 the nasal cytological assessment showed statistically significant improvements in the ciliary motility and in the count of neutrophils and spores in group I, but not in group II. Conversely, there were no significant differences in the count of eosinophils, mast cells, bacteria and biofilm in either group. Our data for the first time focused on the role of crenotherapy in the improvement of cytological assessment of CRS in the elderly.

[Cytomorphological assessment of the epithelial cells of the nasal cavity in the population of urban areas].

There presented results of cytomorphological studies of the mucous membrane of the nasal cavity in children 6-7 years old, 14-15 years old adolescents and adults of all ages (from 20 to 59 years) living in Ekibastuz and the settlement Solnechnyy. Significant unidirectional subatrophic changes in nasal mucosal epithelium were found in 20.6 to 52.63%. Out of 180 examined children and adults in Ekibastuz and the settlement Solnechnyy 42.0% showed an increased number of apoptotic cells. At the same time in 20.9% out of the 110 examined adults in Ekibastuz in nasal epithelium a large number of binuclear and trinuclear cells was revealed, that indicating a high chemical load.

Bioactivation of the nasal toxicant 2,6-dichlorobenzonitrile: an assessment of metabolic activity in human nasal mucosa and identification of indicators of exposure and potential toxicity.

The herbicide 2,6-dichlorobenzonitrile (DCBN) is a potent nasal toxicant in rodents; however, it is not known whether DCBN causes similar nasal toxicity in humans. The tissue-selective toxicity of DCBN in mouse nasal mucosa is largely dependent on target tissue bioactivation by CYP2A5. The human orthologues of CYP2A5, CYP2A6 and CYP2A13, are both expressed in nasal mucosa and are capable of activating DCBN. In this study, we directly determined the ability of human nasal mucosa to bioactivate DCBN. We also tested the suitability of a glutathione conjugate of DCBN (GS-DCBN) or its derivatives as biomarkers of DCBN exposure and nasal toxicity in mouse models. We found that human fetal nasal mucosa microsomes catalyze the formation of GS-DCBN, with a Km value comparable to that of adult mouse nasal mucosa microsomes. The activity of the human nasal mucosa microsomes was inhibited by 8-methoxypsoralen, a known CYP2A inhibitor. GS-DCBN and its metabolites were detected in the nasal mucosa and nasal-wash fluid obtained from DCBN-treated mice, in amounts that increased with escalations in DCBN dose, and they were all still detectable at 24 h after a DCBN treatment (at 10 mg/kg). Further studies in Cyp2a5-null mice indicated that GS-DCBN and its metabolites in nasal-wash fluid were generated in the nasal mucosa, rather than in other organs. Thus, our data indicate for the first time that the human nasal mucosa is capable of bioactivating DCBN and that GS-DCBN and its metabolites in nasal-wash fluid may collectively serve as indicators of DCBN exposure and potential nasal toxicity in humans.

[Cytogenetic monitoring for assessment of human environmental safety].

Cytogenetic monitoring allows to identify groups and individuals with elevated levels of genomic instability, to determine the presence of genotoxic factors in the inspected area to justify the conduct of hygienic measures. An algorithm for cytogenetic monitoring with the usy of multi-organ karyological test, baseline of indices of cytogenetic effect, cell proliferation and apoptosis are presented, the index of accumulation of cytogenetic damage as a the basis for assessment of the three level of risk of cytogenetic abnormalities, is proposed.

Alternative to the gold standard for sinus augmentation: osteotome sinus elevation.

The development of sinus augmentation procedures has diminished the problem of proper implant placement in the posterior maxilla in patients that have a pneumatized maxillary sinus and reduced alveolar bone. The gold standard approach to augmentation--the external sinus augmentation--was developed years ago and is still touted as the best approach for creating maxillary posterior bone. However, external sinus augmentation procedures are often quite traumatic, time-consuming, and costly, and they have anatomical limitations and considerable documented morbidity. This article discusses the external procedure and contrasts it with an internal sinus augmentation with osteotomes that is as effective in promoting sinus augmentation, is localized and relatively atraumatic, can be performed rapidly, is reasonable in cost, and has negligible morbidity. In addition, a modification of future site development augmentation, in preparation for secondary implant placement, is described, as are three cases, to demonstrate the impressive augmentation that can be achieved with osteotome sinus elevation.

Assessment of genotoxic effects and changes in gene expression in humans exposed to formaldehyde by inhalation under controlled conditions.

Forty-one volunteers (male non-smokers) were exposed to formaldehyde (FA) vapours for 4 h/day over a period of five working days under strictly controlled conditions. For each exposure day, different exposure concentrations were used in a random order ranging from 0 up to 0.7 p.p.m. At concentrations of 0.3 and 0.4 p.p.m., four peaks of 0.6 or 0.8 p.p.m. for 15 min each were applied. During exposure, subjects had to perform bicycle exercises (∼80 W) four times for 15 min. Blood samples, exfoliated nasal mucosa cells and nasal biopsies were taken before the first and after the last exposure. Nasal epithelial cells were additionally sampled 1, 2 and 3 weeks after the end of the exposure period. The alkaline comet assay, the sister chromatid exchange test and the cytokinesis-block micronucleus test were performed with blood samples. The micronucleus test was also performed with exfoliated nasal mucosa cells. The expression (mRNA level) of the glutathione (GSH)-dependent formaldehyde dehydrogenase (FDH, identical to alcohol dehydrogenase 5; ADH5; EC 1.2.1.46) was measured in blood samples by quantitative real-time reverse transcription-polymerase chain reaction with TaqMan probes. DNA microarray analyses using a full-genome human microarray were performed on blood samples and nasal biopsies of selected subgroups with the highest FA exposure at different days. Under the experimental conditions of this study, inhalation of FA did not lead to genotoxic effects in peripheral blood cells and nasal mucosa and had no effect on the expression of the FDH gene. Inhalation of FA did also not cause alterations in the expression of genes in a microarray analysis with nasal biopsies and peripheral blood cells.

[Study of nasal and tonsillar mucosal microbiocenoses as one of the health indices].

The qualitative and quantitative compositions of nasal and tonsillar mucosal biocenoses were studied in healthy individuals and patients with chronic tonsillitis as an ecological criterion for assessing the stability of biocenosis and human health. The qualitative composition of tonsillar mucosal biocenosis turned out to be steady-state both in health and disease. The human nasal mucosa showed itself as an indicator system. Staphylococcal strains with a high persistent potential and polyantibiotic resistance, which may cause an exacerbation of the inflammatory process on translocation to the tonsillar mucosa, were selected on the nasal mucosa of patients with chronic tonsillitis.

Does unrestrained single-chamber plethysmography provide a valid assessment of airway responsiveness in allergic BALB/c mice?

BACKGROUND: Unrestrained plethysmography has been used to monitor bronchoconstriction because of its ease of use and ability to measure airway responsiveness in conscious animals. However, its reliability remains controversial. OBJECTIVE: To investigate if unrestrained plethysmography could provide a valid interpretation of airway responsiveness in allergic BALB/c mice. METHODS: Ovalbumin sensitized BALB/c mice were randomized to receive either a single-dose Ovalbumin challenge (OVA-1D group) or a three-dose Ovalbumin challenge (OVA-3D group). The OVA-1D group was further divided into OVA-1D-I (measured invasively, using lung resistance as the index of responsiveness) and OVA-1D-N group (measured non-invasively, using Penh as the index of responsiveness). Similarly the OVA-3D group was divided into OVA-3D-I and OVA-3D-N groups based on the above methods. The control groups were sensitized and challenged with normal saline. Bronchial alveolar lavage fluid was taken and airway histopathology was evaluated for airway inflammation. Nasal responsiveness was tested with histamine challenge. RESULTS: Compared with controls, a significant increase in airway responsiveness was shown in the OVA-1D-N group (P < 0.05) but not in the OVA-1D-I group. Both OVA-3D-I and OVA-3D-N groups showed higher responsiveness than their controls (P < 0.05). The nasal mucosa was infiltrated by eosinophic cells in all Ovalbumin immunized groups. Sneezing or nasal rubbing in allergic groups appeared more frequent than that in the control groups. CONCLUSION: Penh can not be used as a surrogate for airway resistance. The invasive measurement is specific to lower airway. Penh measurement (done as a screening procedure), must be confirmed by a direct invasive measurement specific to lower airway in evaluating lower airway responsiveness.

An intranasal irritation assessment of antibacterial ointment alone or in combination with mupirocin versus Bactroban Nasal in rabbits.

The purpose of this study was to evaluate the potential irritating effects and the systemic exposure level of an antibacterial ointment containing REP8839 as a single agent or in combination with mupirocin versus Bactroban Nasal in rabbits. Additionally, the reversibility of REP8839 effects during a 14-day recovery period was assessed. Five treatment groups of six male and six female New Zealand White rabbits received dose levels of 1%, 2%, and 4% REP8839, 2% Bactroban Nasal, or 2% REP8839/2% mupirocin combination. One additional group of six animals/sex served as the control and received the vehicle, Petrolatum/Softisan 649. The test article or vehicle was administered to all groups via topical administration to the external nares, twice a day (approx. 8h intervals between the doses) for 21 consecutive days, at a dose volume of 100 microL per nare/dose for a total of 400 microL per day (200 microL per nare). Two animals/sex/group were maintained for a 14-day recovery period. The external nares were reflected back and the mucosal lining was evaluated and scored for erythema and edema within 30-60 min following the first dose each day. Blood samples were collected from all animals at designated time points on Day 21 of the study to assess systemic exposure levels. Cross-sectioning of the nasal tract was conducted in all the groups for microscopic evaluation. Mucosal scoring of the nares did not reveal any edema or erythema in any of the dose groups with the antibacterial alone, with the combination product, or with Bactroban Nasal. Mean body weights and food consumption were not adversely impacted by the test articles. Minimal plasma exposure was observed in the rabbits (<5 ng/mL). The REP8839 groups did appear to have dose-responsive exposure (from below the limit of quantitation to 5 ng/mL with 1%, 2%, and 4% REP8839, respectively). Microscopic changes on the nasal sectioning noted in these animals were infrequent and considered incidental findings unrelated to administration of the test articles. In conclusion doses of up to 4% of REP8839 ointment as a single agent or 2% in the combination product, as well as 2% Bactroban Nasal, were not found to induce mucosal irritation when applied topically to the external nares twice a day for 21 consecutive days. Additionally, no delayed effects were observed in the recovery animals.