The Effects of Systemic, Topical, and Intralesional Steroid
Transkript
The Effects of Systemic, Topical, and Intralesional Steroid
Otolaryngology http://oto.sagepub.com/ -- Head and Neck Surgery The Effects of Systemic, Topical, and Intralesional Steroid Treatments on Apoptosis Level of Nasal Polyps Burak Kapucu, Engin Cekin, Bulent Evren Erkul, Hakan Cincik, Atila Gungor and Ufuk Berber Otolaryngology -- Head and Neck Surgery 2012 147: 563 originally published online 2 May 2012 DOI: 10.1177/0194599812446678 The online version of this article can be found at: http://oto.sagepub.com/content/147/3/563 Published by: http://www.sagepublications.com On behalf of: American Academy of Otolaryngology- Head and Neck Surgery Additional services and information for Otolaryngology -- Head and Neck Surgery can be found at: Email Alerts: http://oto.sagepub.com/cgi/alerts Subscriptions: http://oto.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav >> Version of Record - Aug 29, 2012 OnlineFirst Version of Record - May 2, 2012 What is This? Downloaded from oto.sagepub.com at SOCIEDADE BRASILEIRA DE CIRUR on October 29, 2012 Original Research—Sinonasal Disorders The Effects of Systemic, Topical, and Intralesional Steroid Treatments on Apoptosis Level of Nasal Polyps Otolaryngology– Head and Neck Surgery 147(3) 563–567 Ó American Academy of Otolaryngology—Head and Neck Surgery Foundation 2012 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0194599812446678 http://otojournal.org Burak Kapucu, MD1, Engin Cekin, MD1, Bulent Evren Erkul, MD1, Hakan Cincik, MD1, Atila Gungor, MD1, and Ufuk Berber, MD2 No sponsorships or competing interests have been disclosed for this article. Abstract Objective. The purpose of this study was to compare the apoptotic responses to systemic, topical, and intrapolyp injection of glucocorticoid with no treatment in nasal polyps. Study Design. Prospective, randomized controlled study. Setting. Tertiary training hospital. Subjects and Methods. The study was performed on 48 patients with nasal polyposis in the Department of Otorhinolaryngology between 2008 and 2009. Patients were assigned to 1 of 4 groups of 12 patients. Group A was treated with oral methylprednisolone 1 mg/kg/d, and the dose was tapered gradually. Group B received 0.3 mL triamcinolone acetonide (40 mg/mL), which was injected into polyp tissue. Group C was treated with topical 55 mg triamcinolone acetonide 2 times daily for 1 month. Group D received no medication. Samples were collected endoscopically after the seventh day for groups A and B, the first month for group C, and the first visit for group D. Apoptotic indexes were determined using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method. Results. Statistically significant differences in apoptotic index were found between each steroid-medicated group and the control group (PD-A = .0001; PD-B = .003; PD-C = .026) and between groups A and C (PA-C = .012). Group B did not differ significantly from either group A or C (PA-B = .11; PB-C = .75). Conclusions. The apoptotic index in nasal polyps treated with systemic, topical, and intrapolyp injection forms of glucocorticoids was higher than that in the control group. Systemic steroid treatment induced the most apoptosis. Keywords nasal polyp, nasal polyposis, corticosteroid, intralesional, topical, systemic, apoptosis Received January 6, 2012; revised March 23, 2012; accepted April 6, 2012. N asal polyposis (NP) is defined by an edematous mass caused by chronic inflammation and is characterized by nasal mucosal metaplasia, secretory hyperplasia, inflammatory cell infiltration (mostly eosinophils, lymphocytes, and plasmocytes), increased fibroblast production, extracellular matrix deposition, and fibrosis.1 The prevalence of NP is 1% to 4%,2,3 and it is seen almost equally in all races and social classes. Steroids are considered to be the most effective antiinflammatory drugs. The effects of steroids on NP have been reported, and they are currently the most common drugs used to treat NP.3 Topical sprays and oral and intrapolyp-injected forms of glucocorticoids are used in treating NP. Apoptosis is physiological cell death caused by developmental and environmental stimuli that activate cell suicide programs in multicellular organisms.4 Apoptosis is an important process in the reduction of inflammatory cells and resolution of the inflammatory processes. Induction of apoptotic cell death has been shown to accompany resolution of the inflammatory process in inflammatory diseases of the respiratory system such as nasal polyposis. Steroids are known to induce apoptosis of fibroblasts and inflammatory cells in NP tissue, remove these cells, and resolve inflammation in nasal polyp tissue.5-11 We compared the different forms of steroid treatments with each other and with no treatment to demonstrate their effects on apoptosis in polyp tissue. Subjects and Methods This prospective, controlled study was performed on 48 patients (40 men, 8 women) who had NP. The age range was 20 to 60 years (mean, 32.2 years). The GATA Medical 1 Department of Otorhinolaryngology, GATA Haydarpasa Training Hospital, Istanbul, Turkey 2 Department of Pathology, GATA Haydarpasa Training Hospital, Istanbul, Turkey This study was presented as a poster presentation at the 2010 AAO-HNSF Annual Meeting & OTO EXPO; September 26-29, 2010; Boston, Massachusetts. Corresponding Author: Bulent Evren Erkul, MD, GATA Haydarpasa Egitim Hastanesi, KBB klinigi 34668 Kadikoy, Istanbul Email: [email protected] Downloaded from oto.sagepub.com at SOCIEDADE BRASILEIRA DE CIRUR on October 29, 2012 564 Otolaryngology–Head and Neck Surgery 147(3) Faculty (Ankara-Turkey) Drug Research Local Ethics Committee approved the study (12/2008-90), and all patients gave signed informed consent. Exclusion criteria were as follows: past surgeries for NP, any glucocorticoid usage for any reason within 1 month, nasal polyp that was not eosinophilic NP according to the pathology study, fungal chronic sinusitis, age younger than 15 years, Churg-Strauss syndrome, immunodeficiency, Kartagener’s syndrome, Young’s syndrome, cystic fibrosis, antrochoanal polyp, and unilateral nasal polyp. Additional exclusion criteria were any contraindications for steroid treatment (such as glaucoma, peptic ulcer, acute psychosis, herpetic keratitis, chronic infections, severe osteoporosis, severe hypertension, uncontrolled diabetes mellitus, thromboembolic predisposition, newly formed bowel anastomosis, diverticulitis, and Cushing’s syndrome). All patients completed a detailed questionnaire regarding exclusion criteria. All patients assigned to oral steroid were checked before starting medication with complete blood testing, including hemoglobin, hematocrit, leukocyte and thrombocyte counts, glucose, urea, creatinine, direct and indirect bilirubin, liver enzymes, total cholesterol, lipid profile, and blood pressure. Any complications seen during treatment were recorded. All patients had paranasal computed tomography for diagnosis before the treatment, but we did not do a radiological evaluation after the treatment. Treatment Protocols and Material Collection Patients with NP were randomly assigned to 4 groups of 12 patients. Group A was treated with oral methylprednisolone (Prednol 16-mg tablet, Prednol 4-mg tablet; Mustafa Nevzat Pharmaceutical, Istanbul, Turkey) 1 mg/kg/d. The dose was applied for 3 days and tapered gradually, with a reduction rate of 8 mg/3 days, and so duration of drug use varied for each patient changing according to his or her weight. Lansoprosol (Lansor 30-mg capsule; Sanovel Pharmaceuticals, Istanbul, Turkey) 30 mg/d was given to patients in group A during oral steroid treatment to avoid the possible gastrointestinal side effects of methylprednisolone. Group B received intrapolyp steroid injections. Two puffs of xylometazoline hydrochloride (Otrivine Adult Nasal Spray 0.1%; Novartis Pharmaceuticals, Istanbul, Turkey) were applied into both nasal cavities once for vasoconstriction. After 5 minutes, 0.3 mL triamcinolone acetonide (Kenacord-A 40-mg/mL ampoule; Bristol-Myers Squibb, Istanbul, Turkey) was injected into polyp tissue in both nasal cavities with the help of an endoscope. Injections were placed in the central area of well-visualized polyps, and care was taken to avoid injection into vessels. A 27gauge, 50-mm dental needle with a 2-mL syringe was used. This procedure was recorded endoscopically using a video recorder to take samples from the same polyps after treatment. Nasal tampons (Sauger surgical patties; Medikokim, Istanbul, Turkey) were used when bleeding occurred. Group C was treated topically with 55 mg triamcinolone acetonide spray (Nasacort AQ Spray; Sanofi-Aventis, Istanbul, Turkey) 2 times daily with 2 puffs in both nasal cavities for 1 month. Group D was the control group, and no medication was given. Samples from group A were collected endoscopically on the seventh day to ensure sampling before possible complete disappearance of the polyps. Video-guided sample collection from group B was also performed on the seventh day. Samples from group C were collected at the end of the first month from polyps that were located anteriorly in any nasal cavity. Samples from group D were taken at each patient’s first visit to the clinic. A piece of each polyp was sent to the pathology laboratory for study. The rest of the samples were stored at –80°C prior to immunohistochemical analysis. Immunohistochemical Preparation of Samples and Detection of Apoptosis Paraffin blocks were prepared for each sample. Pathologic examination confirmed the diagnosis of eosinophilic NP. Threemillimeter-thick paraffin block samples were prepared and mounted on positively charged microscope slides. Apoptotic cells were detected by using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method with the ApopTag Plus Peroxidase kit (In Situ Apoptosis Detection Kit; Chemicon International, Temecula, California). Approximately 1000 stromal cells were counted in the most intense TUNEL staining areas using a Nikon light microscope (Nikon USA, Melville, New York) at 4003. The percentage of apoptosis-positive cells (brown stained, oval to round in shape, with narrow/dense cytoplasmic nuclear condensation and fragmentation) was determined, and this result was the apoptotic index (Figure 1). Statistical Analysis Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS, version 15.0; SPSS, Inc, an IBM Company, Chicago, Illinois). Means, modes, medians, standard deviations, proportions, and percentages were determined as applicable. The means and standard deviations were calculated for continuous variables, whereas ratios and proportions were calculated for categorical variables. Proportions and ratios were compared using 1-way analysis of variance (ANOVA), post hoc Dunnett’s test, and Scheffé’s post hoc test. P values less than .05 were taken as statistically significant. Results All participants completed the study. No systemic or local side effects of steroid treatment were seen in any patients. We did not detect any complications related to vision in group B. Anterior nasal packing was not required for epistaxis, which occurred during sampling. The apoptotic indexes of all groups were normally homogeneously distributed (P = .08) (Table 1). We compared the apoptotic indexes of groups A, B, and C with those of the control group (group D) to examine the effects of steroid treatments. We found statistically significant Downloaded from oto.sagepub.com at SOCIEDADE BRASILEIRA DE CIRUR on October 29, 2012 Kapucu et al 565 Figure 1. Nasal polyp tissue samples stained with deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). 3#-OH DNA ends generated by DNA fragmentation apoptotic cells can be seen in black and are marked with arrows. There was intense apoptosis in A and rare apoptosis in B. Table 1. Apoptotic Index of Each Group Groups No. Apoptotic Index, Mean 6 SD (Min-Max) SS IPI SPR Control SS, IPI, SPR 12 12 12 12 36 32.50 6 9.32 (10-48) 22.50 6 11.21 (7-42) 19 6 13.05 (6-50) 7.92 6 4.74 (0-15) 24.67 6 12.41 (6-50) Abbreviations: IPI, intrapolyp injection; Min, minumum; Max, maximum; SPR, spray; SS, systemic steroid. Figure 3. Error bars of the groups’ apoptosis indexes with the 95% confidence interval. IPI, intrapolyp injection; SPR, spray; SS, systemic steroid. Figure 2. Comparison of the distribution of apoptosis indexes among groups. The x-axis shows the groups and the y-axis shows the apoptosis index values of the groups. IPI, intrapolyp injection; SPR, spray; SS, systemic steroid. differences in apoptotic indexes between groups D and A (PD-A = .0001), groups D and B (PD-B = .003), and groups D and C (PD-C = .026) (Figure 2 and Figure 3). The data from all steroid treatment groups were combined into 1 group (group ABC) (Table 1), and the resulting apoptosis index was compared with that of the control group (group D). We found a statistically significant difference in the apoptotic index between group D and group ABC (PD-ABC = .0001). When all steroid treatment groups (A, B, and C) were compared with each other, we found that group C had the lowest mean scores (19 6 13.05) (Table 1). We found a statistically significant difference in the apoptosis index between groups A and C (PA-C = .012). There was no statistically significant difference in the apoptotic index between groups B and C (PB-C = .75) or between groups B and A (PA-B = .11). Discussion Nasal polyposis is the most common cause of mass lesions in the nasal cavity, and the prevalence of NP is approximately Downloaded from oto.sagepub.com at SOCIEDADE BRASILEIRA DE CIRUR on October 29, 2012 566 Otolaryngology–Head and Neck Surgery 147(3) 1% to 4%.12 Larsen and Tos3 found that the incidence of NP increases with age and estimated the overall incidence of symptomatic nasal polyps as 0.627/1000 per year. The incidence increases after age 20 years and declines after age 60 years, with the disease most commonly diagnosed in patients 42 years of age.12-14 Our study included 40 male and 8 female patients; the mean age was 32.2 years. Today, medical, surgical, or combination modalities are used in treating NP. The main objectives are the elimination of polyps, maintenance of sinus drainage and nasal breathing, and prevention of recurrence. Corticosteroids are one of the medical treatment modalities that have a proven effect on the symptoms and signs of nasal polyps. They can be used topically or systemically or be injected into the polyp tissue. Intranasal steroid injection was first described in the 1950s. It can be used as an intraturbinal injection for allergic rhinitis or as an intrapolyp injection for NP. The first reports of visual loss as a complication of nasal steroid injection followed in the 1960s.15,16 Guidelines included the choice of a steroid with a small particle size such as triamcinolone acetonide, use of a narrow-gauge needle, and use of a topical vasoconstrictor to reduce nasal vascular congestion before injection. Triamcinolone acetonide has the advantage of being a suspension of small particles with local effects that last for several weeks.17-20 Topical vasoconstrictor was applied before triamcinolone acetonide injection, and we used a narrow-gauge needle to avoid complications in our study. No visual complications occurred in our patients treated with 0.3 mL triamcinolone acetonide injected into the polyp tissue. Methylprednisolone and dexamethasone are the most commonly used systemic corticosteroids for NP. Van Camp and Clement21 treated 25 patients with NP with 60 mg oral prednisolone with a progressive reduction of the dose (–5 mg/d) over 4 days. Seventy-two percent of the patients showed subjective improvement. Tuncer et al22 evaluated the efficacy of oral methylprednisolone on NP and concluded that steroids could delay the necessity for surgical intervention. We preferred to use oral methylprednisolone 1 mg/kg/d for systemic steroid treatment and taper the dose gradually. We did not encounter any side effects during oral steroid treatment. Many studies have been conducted on the effects of various nasal steroid sprays in NP treatment, with multiple placebo-controlled studies demonstrating significant success.23-26 The use of topical corticosteroids in NP was first reported by Mygind et al.23 In their double-blind study with beclomethasone dipropionate aerosol, they found the effectiveness of the drug to be 80% vs 13% for the placebo in a 3-week period. Herman25 compared the efficacy, safety, patient preference, and cost-effectiveness of once-daily budesonide aqueous nasal spray, fluticasone propionate nasal spray, mometasone furoate nasal spray, and triamcinolone aqueous nasal spray for treatment of allergic rhinitis in adult patients. They have found that these steroid sprays had similar efficacy and safety profiles. We did not find a study involving apoptosis and triamcinolone acetonide in nasal polyps. Furthermore, topical triamcinolone acetonide produced statistically significant reductions in symptoms relative to placebo in a 4-week treatment period in subjects with allergic rhinitis.27 We used 55 mg triamcinolone acetonide topically 2 times daily for 1 month in each nasal cavity in group C. In our study, we did not encounter any side effects in the triamcinolone acetonide nasal spray group. As the distribution and effectiveness of the spray are not homogeneous, especially in the rear areas of the nasal cavity in those with common polyps, the samples were collected from the polyps closest to the entrance of the nasal cavity to achieve optimum results from the intranasal steroid spray. Apoptosis is important in both the topical and the systemic steroid treatment of NP.5-11 However, there are no prior published comparisons of the apoptotic effects of topical and systemic steroid treatments in vivo. We attempted to identify the effects of oral, intranasal, and intrapolypinjected steroids in the treatment of patients with nasal polyps by comparing their apoptotic rates in vivo with each other and with the control group. Nittoh et al28 found that dexamethasone, methylprednisolone, and hydrocortisone were similarly effective in inhibiting rat eosinophil survival and enhancing apoptosis in culture. More recently, Hirano et al8 had incubated polyps with beclomethasone, dexamethasone, testosterone, and estradiol in vitro. Using DNA fragmentation to determine the percentage of apoptotic cells, they observed that 20% of the cells were apoptotic in the presence of dexamethasone and beclomethasone, whereas apoptosis was not induced by testosterone or estradiol. When we combined all our data from the steroid-treated groups and compared the resulting apoptotic index with that of the control group, we found a statistically significant difference between them (PD-ABC = .0001), showing that steroid treatment increased apoptosis in polyp tissue. Saunders et al27 demonstrated increased apoptosis in inflammatory cells of nasal polyps after steroid application in vitro. In their double-blind, randomized study, patients with NP were assigned to 1 of 2 groups: 1 group received fluticasone propionate spray for 14 days, and the other group was designated the control group. Specimens were collected from both groups during nasal polypectomy for calculating the apoptotic index using the TUNEL method. No significant difference in the apoptotic index was found. In the same study, NP samples from 5 patients were cultured in media containing various concentrations of dexamethasone, and the apoptotic indexes of the cells were assessed by use of the TUNEL method at different times. The apoptotic index increased with elevated dexamethasone concentration and time. Watanabe et al10 showed that the administration of topical steroids in vivo increased the apoptotic index of eosinophils and T lymphocytes in nasal polyps. Fan et al11 collected samples from patients with allergic sinusitis before and after oral prednisone 20 mg/d. Using the TUNEL method, they showed increased eosinophilic apoptosis after treatment. We observed a statistically significant increase in the apoptotic index in all steroid treatment groups compared with the control group and Downloaded from oto.sagepub.com at SOCIEDADE BRASILEIRA DE CIRUR on October 29, 2012 Kapucu et al 567 found that the topical steroid spray induced less apoptosis than did the systemic or intralesional steroid. The difference between systemic steroid and steroid spray in the induction of apoptosis was statistically significant. We did not compare size of polyps in this study because of the different anatomic distributions of the different forms of steroid: systemic steroid treatment affects all polyps, steroid injection affects mostly the area around the injection, and the steroid spray reaches the most anteriorly located polyps. Conclusion Systemic, topical, and intrapolyp injection forms of glucocorticoids induced apoptosis in nasal polyp tissue when compared with the control group. We found that systemic steroid treatment induced the most apoptosis. There was no statistically significant difference in the apoptotic index between oral and intrapolyp delivery. Author Contributions Burak Kapucu, substantial contributions to conception and design, acquisition of data and analysis, drafting the article, final approval of the version; Engin Cekin, substantial contributions to conception and design, drafting the article, final approval of the version; Bulent Evren Erkul, analysis and interpretation of data, drafting the article and revising, final approval of the version; Hakan Cincik, substantial contributions to conception and design, revising, final approval of the version; Atila Gungor, substantial contributions to conception and design, revising, final approval of the version; Ufuk Berber, acquisition of data and analysis, revising, final approval of the version. Disclosures Competing interests: None. Sponsorships: None. Funding source: None. References 1. Seethala RR, Pant H. Pathology of nasal polyps. In: Önerci M, Ferguson BJ, eds. Nasal Polyposis. New York: Springer; 2006: 17-26. 2. Dingsor G, Kramer J, Olsholt R, Soderstrom T. Flunisolide nasal spray 0.025 % in the prophylactic treatment of nasal polyposis after polypectomy: a randomized, double blind, parallel, placebo controlled study. Rhinology. 1985;23:49-58. 3. Larsen PL, Tos M. Nasal polyps: epithelium and goblet cell density. Laryngoscope. 1989;99:1274-1280. 4. Alles A, Alley K, Barrett JC, et al. Apoptosis: A general comment. FASEB J. 1991;5:2127-2128. 5. Meagher LC, Cousin JM, Seckl JR, Haslett C. Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. J Immunol. 1996;156:4422-4428. 6. Liles WC, Dale DC, Klebanoff SJ. Glucocorticoids inhibit apoptosis of human neutrophils. Blood. 1995;86:3181-3188. 7. Saunders MW, Wheatley AH, George SJ, Lai T, Birchall MA. Do corticosteroids induce apoptosis in nasal polyp inflammatory cells? In vivo and in vitro studies. Laryngoscope. 1999; 109:785-790. 8. Hirano S, Asano K, Namba M, Kanai K, Hisamitsu T, Suzaki H. Induction of apoptosis in nasal polyp fibroblasts by glucocorticoids in vitro. Acta Otolaryngol. 2003;123:1075-1079. 9. Kanai N, Denburg J, Jordana M, Dolovich J. Nasal polyp inflammation: effect of topical nasal steroid. Am J Respir Crit Care Med. 1994;150:1094-1100. 10. Watanabe K, Shirasaki H, Kanaizumi E, Himi T. Effects of glucocorticoids on infiltrating cells and epithelial cells of nasal polyps. Ann Otol Rhinol Laryngol. 2004;113:465-473. 11. Fan GK, Itoh T, Imanaka M, Fujieda S, Takenaka H. Eosinophilic apoptosis in sinus mucosa: relationship to tissue eosinophilia and its resolution in allergic sinusitis. J Allergy Clin Immunol. 2000;106:551-558. 12. Triglia JM, Nicollas R. Nasal and sinus polyposis in children. Laryngoscope. 1997;107:963-966. 13. Larsen K, Tos M. The estimated incidence of symptomatic nasal polyps. Acta Otolaryngol. 2002;122:179-182. 14. Larsen PL, Tos M. Origin of nasal polyps: an endoscopic autopsy study. Laryngoscope. 2004;114:710-719. 15. Hager G, Heise G. A severe complication with permanent practical blindness of one eye following intranasal injection. HNO. 1962;10:325-328. 16. Rowe RJ, Dasler TW, Kinkella AM. Visual changes and triamcinolone. JAMA. 1967;201:117. 17. Kabaker SS. Collected letters of the International Correspondence Society of Ophthalmologists and Otolaryngologists. Soc Ophthalmol Otolaryngol. 1975;20:159-160. 18. Baker DC, Strauss RB. The physiologic treatment of nasal obstruction. Clin Plast Surg.1977;4:121-130. 19. McCleave D, Goldstein J, Silve S. Corticosteroid injections of the nasal turbinates: past experience and precautions. Otolaryngology. 1978;86:851-857. 20. Mabry RL. Intraturbinal steroid injections: indications, results, and complications. South Med J. 1978;71:789-791, 794. 21. van Camp C, Clement PA. Result of oral steroid treatment in nasal polyposis. Rhinology. 1994;32:5-9. 22. Tuncer U, Soylu L, Aydogan B, Karakus F, Akcali C. The effectiveness of steroid treatment in nasal polyposis. Auris Nasus Larynx. 2003;30:263-268. 23. Mygind N, Pedersen CB. Treatment of nasal polyps with intranasal beclomethasone dipropionate aerosol. Clin Allergy. 1975;5:159-164. 24. Waddell AN, Patel SK, Toma AG, Maw AR. Intranasal steroid sprays in the treatment of rhinitis: is one better than another? J Laryngol Otol. 2003;117:843-845. 25. Herman H. Once-daily administration of intranasal corticosteroids for allergic rhinitis: a comparative review of efficacy, safety, patient preference, and cost. Am J Rhinol. 2007;21:70-79. 26. Skoner D, Rachelefsky GS, Meltezer EO, et al. Detection of growth suppression in children during treatment with intranasal beclomethasone dipropionate. Pediatrics. 2000;105:23-26. 27. Meltzer EO, Gallet CL, Jalowayski AA, et al. Triamcinolone acetonide and fluticasone propionate aqueous nasal sprays significantly improve nasal airflow in patients with seasonal allergic rhinitis. Allergy Asthma Proc. 2004;25:53-58. 28. Nittoh T, Fujimori H, Kozumi Y, Ishihara K, Mue S, Ohuchi K. Effects of glucocorticoids on apoptosis of infiltrated eosinophils and neutrophils in rats. Eur J Pharmacol. 1998;354:73-81. Downloaded from oto.sagepub.com at SOCIEDADE BRASILEIRA DE CIRUR on October 29, 2012
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