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Nasal cavity and paranasal sinus have various functions. However, little information is available on ion transport in these upper airway epithelia. In the present study, we measured the anion secretion and the anion channel activity to characterize the ion transport in epithelial cells prepared from human paranasal sinus mucosa (PSM) and nasal polyp (NP). To estimate the anion secretion and the anion channel activity, we measured the short-circuit current (Isc) and the transepithelial conductance (Gt) sensitive to NPPB (a Cl(-) channel blocker). The NPPB-sensitive Isc in PSM was larger than that in NP, correlating to the NPPB-sensitive Gt (Cl(-) channel activity). Forskolin stably elevated the NPPB-sensitive Isc associated with an increase in the NPPB-sensitive Gt in PSM and NP. UTP transiently stimulated the Isc associated with an elevation of Gt in PSM and NP. The stimulatory action of UTP on Isc and Gt was diminished by application of NPPB but not benzamil in PSM and NP, suggesting that UTP induced the NPPB-sensitive Isc (Cl(-) secretion) and Gt (Cl(-) channel activity). These observations suggest that in human PSM and NP, cAMP stably stimulates anion secretion by activating the Cl(-) (anion) channels, and that UTP just transiently elevates anion secretion via activation of some Cl(-) (anion) channels.

In this article, we propose a multivariate generalization of the criteria for testing univariate population bioequivalence. Recently, a number of approaches for testing multivariate equivalence have appeared in the literature. Most of them consider a multivariate equivalence region, which implies simultaneous comparison of means in each dimension. In contrast, our proposal combines a comparison of means and a comparison of variances into a single aggregate criterion, using the trace of the covariance matrix as a scalar measure of the total variability. We use a confidence interval approach to multivariate population bioequivalence testing, similar to the univariate case. Two versions of the modified large-sample confidence interval for the linearized multivariate criterion are constructed. In a simulation study, we evaluate the empirical coverage of these confidence intervals and rejection rates of the corresponding tests in finite samples. The proposed methodology is illustrated with an example of testing equivalence of the spray pattern of nasal sprays., (Copyright (c) 2006 John Wiley & Sons, Ltd.)

Background: Many patients and physicians interpret episodic headache in the presence or absence of nasal symptoms as "sinus' headache, while ignoring the possible diagnosis of migraine., Objective: The purpose of this study was to assess the efficacy and tolerability of sumatriptan succinate 50-mg tablets in patients with migraine presenting with "sinus" headache., Methods: A randomized, double-blind, placebo-controlled, multicenter study was conducted in adult (aged 18-65 years) migraine patients presenting with self-described or physician-diagnosed "sinus" headache. From November 2001 to March 2002, patients meeting International Headache Society criteria for migraine (with > or =2 of the following: unilateral location, pulsating quality, moderate or severe intensity, aggravation by moderate physical activity; and > or =1 of: phonophobia and phonophobia, nausea and/or vomiting) and with no evidence of bacterial rhinosinusitis were enrolled and randomized in a 1:1 ratio via computer-generated randomization schedule to receive either 1 sumatriptan 50-mg tablet or matching placebo tablet. The primary efficacy end point was headache response (moderate or severe headache pain reduced to mild or no headache pain) at 2 hours after administration. The presence or absence of migraine-associated symptoms and sinus and nasal symptoms was also measured. Tolerability was assessed through patient-reported adverse events (AEs)., Results: Two hundred sixteen patients with self-described or physician-diagnosed "sinus" headache received a migraine diagnosis and treated 1 migraine attack with sumatriptan 50 mg. The efficacy (intent-to-treat) analysis included 215 patients treated with sumatriptan 50 mg (n = 108; mean [SD] age, 39.6 [12.3] years; mean [SD] weight, 77.7 [17.7] kg; sex, 71% female; race, 69% white) or placebo (n = 107; mean [SD] age, 41.0 [11.3] years; mean [SD] weight 80.7 [20.9] kg; sex, 69% female; race, 64% white). Significantly more patients treated with sumatriptan 50 mg achieved a positive headache response at 2 and 4 hours after administration compared with those treated with placebo (69% vs 43% at 2 hours and 76% vs 49% at 4 hours, respectively; both, P < 0.001). Significantly more sumatriptan-treated patients were free from sinus pain compared with placebo recipients at 2 hours (63% vs 49% placebo, P = 0.049) and 4 hours (77% vs 55%, P = 0.001). All treatments were generally well tolerated. The most common drug-related AEs reported in the sumatriptan and placebo groups, respectively, were dizziness (5% vs < 1%), nausea (3% vs 2%), other pressure/tightness (defined as sense of heaviness; heaviness of upper body, upper extremities; jaw tension; neck tension) (4% vs 0%), and temperature sensations (defined as warm feeling of back of neck, or flushing) (2% vs 0%). No patients experienced any serious AEs., Conclusions: Sumatriptan 50-mg tablets were effective and generally well tolerated in the treatment of these patients presenting with migraine headaches that were self-described or physician-diagnosed as sinus headaches.

Objective: Determine the efficacy of computerized tomography (CT) in detecting the intranasal distribution of sprayed radio-enhanced particles and the effects of topical decongestion on particle distribution., Study Design: Sinonasal distribution of a radio-enhanced spray solution was studied using CT imaging in 14 adults with no sinonasal symptoms. One nostril was sprayed with oximetazoline 5 minutes prior to particle application. Serial CT imaging of the sinonasal cavity in approximately 11 minutes was carried out to detect particle distribution into the nasal vestibule, turbinate surfaces, middle meatus and osteomeatal complex area, and the nasopharynx., Results: Particle detection within the nasal vestibule was possible in all cases while distribution into the anterior nasal chamber was visible in 22 cases. Particles could be detected on the inferior turbinate in 7 nasal cavities (25%) and in only 2 cases on the middle turbinate (7.5%). Particles were detected in the middle meatus in 1 case and in no instances in the osteomeatal complex area. Oximetazoline application reduced the amount of particle deposition on the inferior turbinate but did not enhance distribution on the middle turbinate or into the middle meatus., Conclusion: Detection of radio-enhanced sprayed particles within the sinonasal cavity using CT imaging can be a reliable method to study the principles of intranasal particle distribution. Our study failed to show particle distribution into OMC, or any positive effects of nasal decongestion on particle distribution.

Background: Allergic rhinitis (AR) is considered a major predisposing factor for the development of acute bacterial rhinosinusitis. How AR augments a bacterial infection is unknown., Objective: Our purpose in this study was to test whether an H1 receptor antagonist, desloratadine, could reduce the augmented effect of an ongoing allergic reaction on acute bacterial rhinosinusitis., Methods: Three groups of infected and ovalbumin (OVA)-sensitized mice were studied: (1) infected and allergic mice treated with desloratadine, (2) infected and allergic mice treated with placebo, and (3) infected mice. A fourth group of uninfected, non-sensitized mice served as a control for the cellular changes. BALB/c mice were sensitized by two intraperitoneal injections of OVA given 8 days apart. One day after the second injection, the mice were nasally exposed daily to 6% OVA (the groups treated with desloratadine or placebo) or phosphate-buffered saline (PBS) (the infection-only group) for 5 days. After the second OVA exposure, the mice were intranasally inoculated with Streptococcus pneumoniae. Desloratadine or placebo was given daily throughout the OVA exposure period. Nasal allergic symptoms were observed by counting of nasal rubbing and sneezing for 10 min after OVA or PBS nasal challenge. On day 5 post-infection, nasal lavage culture was done, and the inflammatory cells in the sinuses were evaluated by flow cytometry., Results: Mice that were made allergic, infected, and treated with placebo showed more organisms and phagocytes than did only infect mice. They also manifested allergic nasal symptoms and eosinophil influx into the sinuses. Desloratadine treatment during allergen exposure reduced allergic symptoms and reduced sinonasal infection (P<0.05). There tended to be less myeloid cell and neutrophil influx (P=0.09 both), but not eosinophil influx (P=0.85) compared with that in the placebo-treated group., Conclusion: Desloratadine treatment during nasal challenge inhibited allergic symptoms and reduced sinonasal infection, suggesting that histamine via an H1 receptor plays a role in the augmented infection in mice with an ongoing allergic reaction.

The aim of this in vitro study was to determine whether the sinus mucosa holds cells with an osteogenic potential. Frozen sections of sinus mucosa from three adult pigs were investigated for the expression of STRO-1, a marker of mesenchymal progenitor cells, and alkaline phosphatase activity, an enzyme expressed by cells committed to the osteogenic lineage and by mature osteoblasts. To determine their osteogenic potential, mucosa-derived cells were incubated with bone morphogenetic protein (BMP)-6 and BMP-7, and alkaline phosphatase activity, osteocalcin expression, and mineralization of the extracellular matrix was measured. We found sinus mucosa cells staining positive for STRO-1 and alkaline phosphatase activity. When sinus mucosa tissue was placed in culture, alkaline phosphatase positive cells grew out from the explants and further increased alkaline phosphatase activity in response to BMP-6 and BMP-7. The expression level of the osteoblast-specific extracellular matrix protein osteocalcin, and the amount of calcium accumulation within the extracellular matrix was also increased in response to BMPs. We conclude that the sinus mucosa holds mesenchymal progenitor cells and cells committed to the osteogenic lineage that can respond to BMP-6 and BMP-7 by an increase of their osteogenic differentiation.

Objective: The spreading of acute respiratory infection into the paranasal sinuses in children is poorly defined. The main objective of this study was to evaluate the frequency and spontaneous resolution of paranasal sinus abnormalities in children with acute respiratory infection using magnetic resonance imaging (MRI)., Methods: We examined 60 children with MRI (mean age: 5.7 years) with symptoms of acute respiratory infection. Twenty-six children with major abnormalities in the first MRI scan had a follow-up MRI taken 2 weeks later., Results: The children had had symptoms of uncomplicated acute respiratory infection for an average of 6 days before the first examination (mean duration: 6.5; standard deviation: 3.0). Approximately 60% of the children had major abnormalities in their maxillary and ethmoidal sinuses, 35% in the sphenoidal sinuses, and 18% in the frontal sinuses. The most common abnormal finding was mucosal swelling. The mean overall MRI scores correlated significantly with the symptom scores (r(s) = 0.3). Of the individual symptoms, nasal obstruction, nasal discharge, and fever were significantly related to the MRI scores. Among the 26 children with major abnormalities in the first MRI, the findings subsequently improved significantly (mean [standard deviation] score: 12.7 [5.6] to 5.7 [5.2]), irrespective of the resolution of symptoms., Conclusions: These observations indicate that acute respiratory infection mostly spreads into the paranasal sinuses of children in the form of mucosal edema and that these abnormalities tend to resolve spontaneously without antimicrobial treatment.

This aim of this study was to evaluate the size and light reflex of the pupils during endoscopic sinus surgery (FESS). Pupil size and light reflexes were recorded prospectively in 20 patients undergoing FESS under general anaesthesia. Nasal mucosal vasoconstriction was induced by Moffett's solution. A control group of 20 patients underwent other standard ENT operations under general anaesthesia. Myosis occurred in all 40 patients after induction of general anaesthesia. During surgery, the light reflex was negative for all 40 patients. However, the light reflex became positive in 22 patients within 5 min of surgery, and in all patients after 20 min. Monitoring pupillary size and reflexes during FESS as a means of assessing trauma to the orbital structures is difficult because of the presence of myosis induced by anaesthetic agents. Moffett's solution did not have a mydriatic effect from the systemic absorption of cocaine during the operative period.

Cocaine abuse may be associated with a destructive nasal and pharyngeal process felt to be due to ischemia secondary to vasoconstriction. This report is the first to document a necrotizing granulomatous vasculitis associated with nasal destruction and an oronasal fistula in a chronic cocaine user. Cocaine is an environmental insult that may play a role in triggering cerebral and non-cerebral vasculitis including a necrotizing granulomatous vasculitis of the respiratory tract.

Although allergic rhinitis is commonly associated most with symptoms of nasal congestion, rhinorrhea, sneezing, and itching, the symptom of sinus pain and pressure often prompts the patient to seek medical attention. The effect of fluticasone propionate on this symptom has not been studied. The purpose of this study was to compare the efficacy and safety of fluticasone propionate aqueous nasal spray to placebo vehicle in the treatment of patients with sinus pain and pressure arising from allergic rhinitis. A multicenter, double-blind, parallel-group trial was conducted in 206 symptomatic patients > or = 12 years with seasonal or perennial allergic rhinitis. Patients were treated for 14 days with either fluticasone propionate aqueous nasal spray, 200 mcg once daily, or placebo vehicle. Patients attended clinic visits and kept diary cards rating sinus pain and pressure (measured as one symptom) and nasal congestion symptoms during the study. Treatment with fluticasone propionate provided significantly greater relief of symptoms of sinus pain and pressure compared with placebo over the entire 14-day treatment period. Nasal congestion scores also were significantly reduced compared with placebo at each time point. Treatments were well tolerated, and the incidence of adverse events attributable to study treatments was similar between groups. Our data indicate that symptoms of sinus pain and pressure and nasal congestion can be significantly reduced in patients with allergic rhinitis when treated with fluticasone propionate aqueous nasal spray, 200 mcg once daily.

Background: Impairment of sinus ostial function is considered an important factor in the pathophysiology of sinus disease. The use of the decongestants such as alpha2-agonists is thought to improve sinus ostial function. Previous studies have shown an effect of alpha2-agonists on maxillary sinus ostial function only when administered in nasal bellows, but not as a nasal spray or nasal drops. The effect of decongestants on ventilation of the frontal and posterior ethmoidal and sphenoidal sinuses has not been studied to date., Methods: In this study, the 133-xenon washout method was used to determine ventilation for all paranasal sinuses before and after administration of oxymetazoline as nasal drops in eight subjects and from nasal bellows in nine healthy subjects., Results: No significant effect of oxymetazoline on sinus ventilation was seen in either group., Conclusions: The results indicate that alpha2-agonists do not have any effect on sinus ventilation in healthy subjects. However, one cannot exclude that decongestants improve sinus ventilation in patients suffering from sinus disease and this requires further studies.

Certain chemotherapeutic agents can induce bizarre epithelial atypia. The lower respiratory tract is a frequently targeted site, but similar changes have not been described adequately in the sinonasal tract. Unfamiliarity with these changes could potentially cause confusion with an infectious or neoplastic process. All biopsies of the sinonasal tract at The Johns Hopkins Hospital were reviewed prospectively over a 54-month period. Eleven cases with bizarre atypia of the respiratory epithelium formed the basis of this study. The medical records of these patients were reviewed. The specimens were from 11 patients who had previously undergone chemotherapy and bone marrow transplantation for acute myelocytic leukemia (n = 5), multiple myeloma (n = 3), acute lymphocytic leukemia (n = 2), and chronic myelocytic leukemia (n = 1). Although the chemotherapy regimens were highly variable, all included one or more of the alkylating agents (cyclophosphamide, n = 11; busulfan, n = 5; melphalan, n = 1). In all 11 patients, biopsies were acquired to rule out invasive fungal sinusitis. The atypical epithelial changes included striking nuclear enlargement, hyperchromasia, and pleomorphism. Sometimes these changes were full thickness and were associated with squamous metaplasia. Two of eight cases evaluated by frozen section were misinterpreted initially as high-grade epithelial dysplasia. Certain chemotherapeutic agents can induce striking epithelial atypia in the sinonasal tract. These changes should not be interpreted as neoplastic in nature, a potential pitfall in the frozen section evaluation of a destructive nasal process in oncology patients.

The technique of controlled hypotonia was developed for adequate management of anesthesia in endonasal microsurgical interventions on the paranasal sinuses in patients with chronic rhinosinusitis. A total of 92 patients with chronic polypous rhinosinusitis aged 18 to 65 years were operated using the following variants of anesthesia: local, local in combination with neuroleptanalgesia and/or ataralgesia with controlled hypotonia, endotracheal oxide-fluoroxene and endotracheal oxide-oxygen anesthesias with neuroleptanalgesia and/or ataralgesia with controlled hypotonia. This was achieved with clofelin. Controlled hypotonia reduces blood loss in endonasal microsurgery on the paranasal sinuses in patients with chronic polypous rhinosinusitis compared to patients unexposed to controlled hypotonia.

To better understand metabolites of arachidonic acid generated from human mast cells, the present study assessed the capacity of human mast cells to synthesize thromboxane B2 (TXB2). Anti-IgE challenge of human sinus mast cells resulted in the generation of TXB2 in a dose-dependent manner with a maximal generation of 8.2+/-4.4 ng/10(6) cells (n = 12), which is about 10-fold lower than the maximal generation of prostaglandin D2 (PGD2). Pretreatment of the cells with OKY-046, an inhibitor of TXA synthase, prevented formation of TXB2 in a dose-dependent manner without affecting the generation of PGD2 or leukotriene C4. Experiments using indomethacin or MK-591, a potent FLAP inhibitor, showed that shunting of arachidonic acid did not occur in a single-cell suspension of mast cells. Analysis by RT-PCR revealed that two species of TXA synthase, the full-length TXA synthase mRNA (TXAS-1, 570 BP) and a small quantity of the alternate-spliced form (400 BP), were present in mast cells. When cellular levels of TXAS-1 mRNA were normalized to those of G3PDH mRNA, the relative concentration of TXAS-1 was 2.06+/-0.60 (n = 7) in highly purified sinus mast cells (92.3+/-3.0% pure) and 3.66+/-0.98 (n = 5) in eosinophils.

Low-dose and long-term administration of 14-lactone-ring macrolides (macrolide therapy) has been reported to be very effective in the treatment of chronic sinusitis, including the sinobronchial syndrome. However, the mechanism whereby the chronic inflammation is down-regulated is unknown. The present study was carried out to immunohistochemically identify the antigens expressed on the surfaces of inflammatory cells in the paranasal mucosa and nasal polyps of patients who responded well to macrolide therapy and in control patients. HLA-DR (a class-II antigen) was detected on relatively large, irregularly shaped cells and on small, round cells in the submucosa. The former cells were considered to be macrophages because they were CD68-positive. Thus, in the paranasal mucosa macrophages act antigen-presenting cells. The numbers of HLA-DR-positive cell and CD68-positive cells varied among the patients and did not differ significantly between the patients who had under gone macrolide therapy and those who had not. There were significantly fewer CD4-positive T lymphocytes in the submucosa of patients who had under gone macrolide therapy than in the control patients, but the number of CD8-positive T lymphocytes did not differ significantly between the two groups of patients. The mean ratio of the number of CD4-positive to the number of CD8-positive T lymphocytes (CD4/CD8) in the submucosa of the patients who had under gone macrolide therapy, 0.77, was significantly lower than in the control patients, 1.92 (< 0.01). HLA-DR expression induces differentiation of and cytokine production by CD4-positive T lymphocytes in the presence of co-stimulators. The present results suggest that macrolides may affect the manner of interaction between antigen-presenting cells such as macrophages and CD4-positive T lymphocytes.

Chronic sinusitis is a persistent inflammatory impairment of the paranasal sinus. Disturbance of the mucociliary function in the paranasal sinus is the most common finding in chronic sinusitis. S-carboxymethylcysteine (S-CMC) has been shown to directly enhance the ciliary activity of the chronic sinusitis mucosa. Direct contact of the disturbed cilia with S-CMC may recover the reduced beating activity of cilia in chronic sinusitis and the mucosal pathology of the disease can thus be improved. Before S-CMC as medicine for nebulization in the treatment of chronic sinusitis can be clinically applied, however, it should be experimentally established whether nebulization of S-CMC has any adverse effects on the mucociliary system of the respiratory mucosa. The present study was designed to experimentally examine the safety of nebulization of S-CMC especially with regard to the respiratory mucosa. Rabbits were treated with nebulization of three different concentrations of S-CMC solution for 20 min a day for 14 successive days, and their mucosal pathology of the sinus and trachea was examined and compared with that of healthy animals. Nebulization of concentrations of 0.5-10% of S-CMC solution did not affect the ciliary activity in the sinus and tracheal mucosa, nor did this treatment induce pathological changes such as epithelial injury and inflammatory cell accumulation. It is therefore concluded that concentrations of 0.5-10% S-CMC solution are quite safe for the use of nebulization in the treatment of chronic sinusitis.

We incubated human paranasal sinus mucosa in tissue culture with each of leukotrienes C4, D4, and E4 (LTC4, LTD4, and LTE4). Ciliary beat frequency (CBF) was measured photoelectrically, and the concentrations of leukotrienes in the incubation medium were determined over time. LTC4 significantly decreased CBF with 2-h, 4-h, and 8-h exposures to 10(-6) M, 10(-8) M, and 10(-10) M, respectively. Moreover, LTC4 dose dependently reduced CBF to 81.4% of the initial value after 6-h exposure to 10(-6) M, to 82.5% after 8-h exposure to 10(-8) M, and to 89.7% after 12-h exposure to 10(-10) M. LTD4 also exhibited progressive ciliary inhibition, while LTE4 had a minimal effect on CBF. In the medium, LTC4 was changed to LTD4 and further to LTE4. gamma-Glutamyl transpeptidase (gamma-GTP), an enzyme that converts LTC4 to LTD4, was detected in the mucosa. Serine-borate complex, an inhibitor of gamma-GTP, blocked the inhibitory effect of LTC4 on CBF. These findings suggest that LTC4 may induce ciliary inhibition indirectly by conversion to LTD4.

Chloroform given by gavage in corn oil at 180 mg/kg per day induced kidney tumors in male Osborne-Mendel rats. Chloroform-induced cytotoxicity and regenerative cell proliferation have been observed in the kidneys of male F-344 rats. In order to compare the acute sensitivity of male Osborne-Mendel with F-344 rats, animals from both strains were administered a single gavage dose of 0, 10, 34, 90, 180, or 477 mg/kg chloroform and necropsied 48 h later. Known target tissues were examined for histological changes. Regenerative cell proliferation was assessed as a labeling index (LI, percent of cells in S-phase) as determined by nuclear incorporation of bromodeoxyuridine. The epithelial cells of the proximal tubules of the kidney cortex were the primary target cells for cytotoxicity and regenerative cell proliferation. A dose-dependent increase in the LI was present in the kidney of Osborne-Mendel rats given doses of 10 mg/kg chloroform and above and in F-344 rats given 90 mg/kg and above. The maximal increase in the LI was 4.5- or 3.7-fold over control in Osborne-Mendel or F-344 given 477 mg/kg, respectively. The only increase in the hepatocyte LI was in the F-344 rats given 477 mg/kg. Edema and periosteal hypercellularity were observed in the nasal passages of both strains at doses of 90 mg/kg and above. These data indicate that Osborne-Mendel and F-344 rats are about equally susceptible to chloroform-induced nephrotoxicity. These results provide a basis for linking the extensive data base on mechanisms of action of chloroform toxicity in F-344 rats to the Osborne-Mendel rat and support the hypothesis that events secondary to chloroform-induced cytolethality and regenerative cell proliferation played a role in the induction of renal tumors in the Osborne-Mendel rat.

In order to study morphological effects on the nasal and sinus mucosa, New Zealand White rabbits underwent either unselective, regional sectioning of sensory and parasympathetic nerve branches or topical treatment of the mucosa with capsaicin. Ten days after treatment, mucosal specimens were analyzed by light and electron microscopy. Immunohistochemistry was used to evaluate neuropeptides present, in particular substance P, calcitonin gene-related peptide, vasoactive intestinal peptide and neuropeptide Y. In surgically denervated rabbits, mucosal glands were found to be enlarged and contained an increased number of zymogen granules having a bipartite substructure. Topical capsaicin application caused localized epithelial changes in the sinus mucosa and maxilloturbinal region of the nose, including clotting of cilia and an increased number of goblet cells. Reduced amounts of all neuropeptides investigated were found in the surgically denervated animals, while topical capsaicin treatment had only marginal effects on the mucosal neuropeptide content. The morphological changes observed after surgical denervation suggest an imbalance between neural stimulation and secretory capacity of the mucosal glands. These findings could explain the difference in clinical effect noted between sectioning of the vidian nerve and topical treatment with capsaicin in patients with perennial rhinitis.

This article has focused on the management of anterior ethmoid and frontal sinus tumors by the otolaryngologist-head and neck surgeon. It emphasizes surgical treatment and describes clinical "pearls and pitfalls" for both the resident and senior clinician. The opinions that we have formulated and that we present herein are based on experience with over 100 cases of tumors of the paranasal sinuses. During this experience, we have utilized and initiated a variety of surgical and reconstructive techniques. Only those that have consistently afforded the best anatomic exposure, surgical flexibility, and reconstructive reliability have been high-lighted and confidently recommended.

The effect of ibudilast (CAS 50847-11-5, 3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine, KC-404), an anti-asthmatic drug, on ciliary beat frequency (CBF) of human paranasal sinus mucosa was examined in vitro. Ciliary activation was observed after a 10-min exposure to 4.6 x 10(-6) mol/l ibudilast. Ibudilast dose-dependently increase CBF at the concentrations ranging from 4.6 x 10(-7) mol/l to 4.6 x 10(-5) mol/l. Propranolol inhibited ciliary activity induced by ibudilast; however, neither indometacin nor verapamil affected the activation of ibudilast on CBF. Platelet activating factor (PAF) and Leukotriene D4 (LTD4) are chemical mediators inducing mucosal dysfunction and damage. Ibudilast prevented ciliary inhibition induced by PAF and LTD4. These findings indicated that ibudilast activates CBF and inhibits the effect of PAF and LTD4 on ciliated cells, and consequently improves the pathogenesis of allergic disorders such as the inhibited mucociliary transport system and airway hyperresponsiveness.

Among macrolide derivatives, azithromycin which is an azalide, is a totally original new drug as to its pharmacokinetics in serum and tissues. Compared to reference compounds such as erythromycin or roxithromycin, pharmacokinetic parameters of azithromycin are characterized by: (i) much lower serum concentrations; (ii) a much longer elimination half-life (48-96 h); (iii) high and persistent tissue concentrations. The latter characteristic has been demonstrated in animal models (experimental H. influenzae pneumonia in mice) and in human studies. In lung parenchyma, azithromycin concentrations were higher and more persistent (72 h) in infected mice (12 mg/kg) as compared to non infected mice (controls) receiving the same dose of azithromycin (50 mg/kg); this may result from high intracellular concentrations in polymorphonuclear leucocytes and release of the drug at pulmonary sites of infection. In man, concentrations of azithromycin have been measured in lung parenchyma, bronchial secretions, tonsils, during exploratory or surgical conditions. After a single dose of 500 mg of azithromycin, local levels may reach up to 10 mg/kg with persistence of high levels for > or = 72 h in lungs, tonsils, sinus and bronchial secretions (1.5 to 8.6 mg/kg or mg/l). Five consecutive doses of azithromycin (500 mg per day) maintained for 10 days tonsil concentrations higher than the MICs for susceptible bacteria.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Fungal sinusitis typically occurs in immunocompromised patients. The authors report four cases of fungal sinusitis in immunocompetent young adults, all of whom had proptosis., Methods: The diagnosis in all four patients was determined after orbital imaging and sinus biopsies., Results: All four patients required surgical removal of the fungal source and anti-fungal chemotherapy postoperatively., Conclusion: Patients with proptosis, ocular pain, or other symptoms suggestive of orbital cellulitis unresponsive to antibiotic treatment should undergo radiographic imaging. If sinus disease is present, biopsy and culture may lead to the diagnosis of fungal disease. Surgical debridement and the appropriate systemic antifungal therapy usually lead to cure.

Aerosol therapy has been widely used for upper and lower airway diseases. However, maximal permissible concentrations of drugs have not yet been clarified. The purpose of this study was to find the maximal drug concentration for transnasal medication that does not inhibit ciliary activity or tissue. Human paranasal sinus mucosa taken at surgery was cut into small pieces. These were cultured in RPMI-1640 medium under the conditions of 5% CO2 and 100% relative humidity at 37 degrees C. Histopathologic damage was observed under a microscope at 400 x magnification. The rate of ciliary beating was measured by a photoelectric method with a cadmium sulphite photometer. In order to compare the findings with those of repeated clinical nebulizer therapy, drug application once a day for 3 days and combined use with steroids were examined for 30 min, considering maximal retention time of the drugs in the nasal cavity as an aerosol therapy. The maximal permissible concentrations of several drugs in single use obtained by these experiments were as follows: acetylcysteine 4.4%, tyloxapol 0.03%, sodium cromoglycate 4%, Broncasma Berna 2 times, prednisolone 1%, dexamethasone 0.2%, betamethasone 0.4%, kanamycin 20%, gentamicine 1%, amikasine 4%, dibekasin 4%, astromysin 4%, fosfomycin 3%, clindamycin 3%, ampicillin 10%, cefazolin 5%, and lidocaine 0.01%. When antibiotics and ateroids were used at the same time, the ciliary activity and the tissue were damaged more strongly than with single use. Therefore, the maximal concentration of some drugs has to be reduced. For example, the maximal concentration of prednisolone, 1%, was reduced to 0.2%, and that of kanamycin, 20%, was changed to 10%.

Low-dose and long-term administration of erythromycin (EM therapy) has been reported to be very effective for patients with intractable chronic sinusitis including sinobronchial syndrome. However, we sometimes encounter patients whose sinusitis is extremely resistant to EM therapy. Therefore, the present study was carried out to determine the correlation between the clinical efficacy of EM therapy and the histopathological features of the ethmoidal mucosa and nasal polyps of patients treated with erythromycin. Patients with significant lymphocytic infiltration in the submucosal area responded well to EM therapy. Furthermore, patients with neutrophilic infiltration within and beneath the ciliary epithelium tended to show improvement with this therapy. On the other hand, EM therapy was minimally effective in patients whose subepithelial layer showed marked eosinophilic infiltration. In patients showing excellent and good clinical results, histological changes in the paranasal mucosa after therapy were as follows: a decrease in the number of inflammatory cells, reduced interstitial edema, increased fibrosis and normalization of the secretory glands. From these results, we conclude that erythromycin may suppress chronic inflammation except for an allergic reaction characterized by marked eosinophilic infiltration.

The effect of leukotriene D4 (LTD4) on human paranasal sinus mucosa was investigated for over 1 hour up to 24 hours using a VTR system at 2,500 X in vitro. Ethmoidal sinus mucosal specimens were incubated in tissue culture, and after exposure to LTD4 the mucosal surface profile was viewed under an inverted phase-contrast microscope equipped with a VTR system on a TVscreen. LTD4-induced ultrastructural alterations, ciliostasis, alterations consisted of a coarse profile and epithelial cell exfoliation. Ciliary activity was photoelectorically measured on the screen hourly. The mucosal specimens were morphologically examined before and after exposure to LTD4 by transmission electron microscopy. LTD4 inhibited ciliary activity in a time- and dose-dependent manner at concentrations ranging from 10(-6)M to 10(-10)M, whereas LTE4 had a minimal effect on the mucosa even at the concentration of 10(-6) M. Irrigation of the mucosa with culture medium after 5-min of exposure to 10(-8) M LTD4 delayed appearance of ciliary inhibition and alteration of the mucosal surface profile, but had no effect after 15-min exposure. These effects of LTD4 on the mucosa were blocked by preincubation with the LT antagonists, FPL-55712 and Ly-171883. These results demonstrate the cytotoxic effect of LTD4 on human airway epithelium in vitro.

Brief information about clinical experience on flunisolide in nasal pathology treatment is presented in this paper. The authors own observations are also included. They describe some cases histories as to how flunisolide can act positively and negatively at on nasal and paranasal clinical pathology.

Over exposure to cadmium may produce numerous adverse health effects, including changes in the nasal mucosa. Cadmium levels were measured in blood and urine samples taken from 106 workers who were exposed to high levels of cadmium and nickel in a cadmium nickel battery plant. Pathological results were observed in 46% and 51% of the blood and urine samples respectively. A positive association was found between clinical nasal complaints and pathological levels of cadmium in blood (P = 0.006) and urine (P = 0.045) samples. All the workers underwent sinus X-rays and 63% of them were abnormal. No correlation was found between pathological sinus X-rays and pathological cadmium level in blood and urine samples. A positive correlation was found between clinical nasal complaints and abnormal sinus X-rays. The prevalence of sinus X-ray abnormalities in an asymptomatic general population is 33% as compared to 63% in our study. This difference is highly significant statistically (P < 0.0001). Our result shows a possible harmful effect of cadmium on the paranasal sinuses.

Twenty mechanically ventilated patients with nosocomial sinusitis were treated with amikacin 15 mg/kg administered either once a day (group 1 patients) or twice a day (group 2 patients). Amikacin was assayed in serum and in the liquid drained from the sinuses 8 times over a 24 hours' period (group 1) or 7 times over a 12 hours' period (group 2). The amikacin concentration peak was 10.9 mg/l in group 1 and 5.1 mg/l in group 2. It is concluded that amikacin can be used to treat patients with nosocomial sinusitis. High amikacin concentrations are reached with the once a day dosage.

The effect of platelet activating factor (PAF) on human paranasal ciliated cells was investigated in vitro. Normal human paranasal sinus mucosa was obtained by surgical procedure and incubated with Eagle's MEM containing 10% FCS in the form of tissue culture. Ciliary activity was viewed at 37 degrees C under an inverted microscope equipped with a thermoregulator and a humidified CO2 chamber, recorded on video tapes and photoelectrically measured. Ciliary inhibition was observed by the treatment with PAF, in a dose dependent manner, at concentrations from 10(-10) M to 10(-6) M. The inhibitory effect of 10(-8) M PAF on ciliary activity was completely blocked when the mucosa was treated with 10(-6) M CV-3988 or 10(-6) M CV-6209 (specific PAF receptor antagonists). By the radioimmunoassay, the concentration of PAF in tissue culture was reduced by half within 12.5 min, and within 60 min it was only 5% of the initial concentration. There was no significant difference in ciliary inhibition between irrigation after a 60 min incubation with 10(-8) M PAF and non-irrigation. These results indicate that PAF inhibited ciliary activity directly and specifically, and induced irreversible damage primarily within the first 60 min after the challenge.

The nose and sinuses are constantly exposed to the huge quantities of gases needed to maintain life. Not only is the human nose well-equipped to warm and humidify this inhaled air, but it is also uniquely able to clean much of it. Any material other than physiologic amounts of oxygen, nitrogen, carbon dioxide, and water that accompanies the airstream can be considered a pollutant, and this pollutant could potentially injure the individual. The following discussion will review the defense mechanisms that allow the nose and sinuses to protect the lower airways. The effects of pollutants on the respiratory mucosa will then be described, including some recent trends in those effects. These trends include specific population consequences of indoor and outdoor air pollution, and changes in risk for individuals in several occupations. Throughout these discussions, specific areas that would benefit from further research will be mentioned.

Human sinus mucosal specimens from eight normal individuals were exposed to platelet activating factor (PAF) at concentrations ranging from 10(-6) M to 10(-11) M in a humidified CO2 chamber at 37 degrees C. The mucosal surface of the specimens was recorded on video tapes and magnified 2,500 times on a 19-inch television (TV) monitor. Ciliary activity of each ciliated cell was photoelectrically measured on the TV monitor in real time. PAF induced mucosal damage which resulted in a coarse profile including ciliostasis and exfoliation of epithelial cells. The length of the incubation period in which the initial coarse profile occurred on the mucosal surface inversely correlated with the concentration of exposed PAF ranging from 10(-6) M to 10(-10) M with r = -0.712 (p less than 2 x 10(-4)). Both the control medium and 10(-8) M lysoPAF showed no effect on ciliary activity or mucosal surface alteration even after 24 hr of exposure. Significant ciliary inhibition was noted after 6 hr of exposure to PAF at concentrations of 10(-8) M and 10(-10) M (p less than 0.05). After 10 hr of exposure, significant ciliary inhibition (p less than 0.01) was noted at all concentrations. Inhibition occurred in a time- and dose-dependent manner. The length of the incubation period in which initial ciliostatis occurred and the level of PAF concentration showed an inverse correlation with r = -0.918 (p less than 10(-6)). These results indicate that PAF is cytotoxic to human respiratory mucosa.

Six mechanically ventilated patients with nosocomial sinusitis received an intravenous infusion of 4 g of piperacillin. Piperacillin concentrations were measured in the serum and in drained sinusal fluid 1, 2, 3, 4, 6 and 8 hours after the beginning of the infusion. A peak piperacillin level of 33 mg/l was obtained 30 minutes after the end of administration, and concentrations of 14 mg/l or more persisted for up to 8 hours. It is concluded that piperacillin can be used to treat patients with nosocomial sinusitis.

A model of wound healing in the maxillary antrum of the rabbit was developed. The regeneration of standardized circular mucosal defects 4 mm in diameter was studied using conventional histology and serial sections as well as three-dimensional histomorphological analysis. Wound closure started by migration of epithelium; 24 h later mitoses were seen. 120 h after creation of the wound the granulation tissue covering the wound surface started to become hyperplastic, and bone apposition with formation of osteoid occurred. Systemic application of prednisolone i.m. (2 mg/kg per day) and topical administration of dexpanthenol-ointment (5%) resulted in an acceleration of the late epithelial wound closure together with a reduction of hyperplastic granulation tissue. Epidermal growth factor, applied locally, had no significant effect. The proposed animal model permits additional quantitative evaluation of postoperative treatment modalities.

Out of 227 cases of nonepithelial tumors of the nasal cavity and paranasal sinuses, 147 patients with benign neoplasms had a good prognosis while 80 patients with malignant neoplasms had a poor prognosis. The efficacy of their therapy can be enhanced on the basis of a differential approach, measurement of tissue radiosensitivity and adequate surgical intervention.

The effect of xylometazolin spray (OTRIVEN) on the nasal mucosa was tested on persons with and without clinical signs of rhinitis and sinusitis. MRI is an excellent means to show the decongestive effect. The reaction is chiefly seen at the inferior and middle nasal concha and becomes manifest in a few minutes. No significant effect is noticeable at the maxillary sinus mucosa and infiltrated ethmoidal sinus. Generally, it is possible to show and examine the pharmacological effects that change the size and the liquid consistency of organs.

The time required for mucociliary clearance from the chicken nasal turbinate and from the maxillary sinus was investigated in individual animals by using a newly designed plastic holder for the experimental animals. Determined in this way were: 1) the effect of SO2 exposure on sinus and turbinate clearance time, 2) the effect of the nerve blocking drugs atropine, scopolamine, reserpine, and propranolol on turbinate clearance time, and 3) the effect of these nerve blockers on clearance rates in chickens exposed to SO2. Turbinate mucociliary clearance was measured at 5 intervals per day, during 1 to 7 hr after exposure, for 7 consecutive days. Sinus clearance time was measured twice daily 1 to 4 hr after exposure. Turbinate clearance time in birds exposed to 6 ppm, and sinus clearance time in birds exposed to 40 ppm intermittently for 2 consecutive days both increased strikingly as a direct effect of SO2 exposure. However, continuous exposure to 6 ppm of SO2 during 16 hr per day for 7 consecutive days produced double peaks of increased turbinate clearance time with intervening recovery periods, suggesting an intranasal mucociliary homeostatic response. In individual animals, 26 of 35 animals (75%) exposed to 5 ppm, and 5 of 10 animals (50%) exposed to 20 ppm continuously during 16 hr per day for 7 consecutive days showed the same patterns. Reserpine and propranolol, which are sympatholytic agents, produced decelerated intranasal transport rates. Atropine and scopolamine, which are parasympatholytic agents, did not affect clearance rates. These nerve blockers, however, blocked the biphasic recovery pattern due to SO2 exposure. This blocking effect was statistically significant for atropine and reserpine 1 hr after injection.

The hypothesis that homeostatic control mechanisms control mucociliary function in ciliated mucous membranes was induced artificially by means of mechanical stimulation. The edge of right palatine cleft was stimulated mechanically by gentle touching with a dissecting needle, and sinus clearance time was recorded as soon as mechanical stimulation was initiated. Mechanical stimulation caused acceleration of mucociliary flow of the sinus; sinus clearance time was accelerated on the side adjacent to the mechanically stimulated side of the palatine cleft, but not on the opposite side. Therefore, the reflex may be effective only on the stimulated side. We investigated the effect of nerve blockers on mechanical stimulation. Mucociliary clearance in the chicken sinus was not affected by parasympatholytic agents, but was decelerated by the beta-adrenergic blocker. The effect of nerve blockers on the mechanical stimulation showed that parasympatholytic agents blocked mechanical stimulation, while sympatholytic agents did not completely block the response. These data suggest that mucociliary clearance may be regulated by the reflex of parasympathetic and partially sympathetic nerve fibers.

The relation of ciliary activity to the partial pressure of carbon dioxide was studied with a photoelectric method on rabbit sinus mucosa in vitro. A dose-response relationship was found, where by ciliary activity was impaired at pCO2 above 5 kPa. The effect of elevated partial pressure of carbon dioxide on ciliary activity in secretory otitis media and sinusitis is discussed.