[Clinical efficacy of a herbal drug combination in acute viral rhinosinusitis]. / Klinische Wirksamkeit eines pflanzlichen Kombinationspräparates in der Behandlung der akuten viralen Rhinosinusitis.

BACKGROUND: Acute rhinosinusitis is a frequent inflammatory disease of the mucosa of the nose and paranasal sinuses, usually associated with substantial morbidity having considerable socioeconomic impact. A new herbal drug based on a dry extract of a combination of 5 medicinal drugs (Sinupret® extract Dragees) was tested in a confirmatory trial in patients with acute viral rhinosinusitis. METHODS: 386 patients with symptomatic acute viral rhinosinusitis have been treated with the herbal drug combination (daily dosage 3 × 160 mg) or placebo in a double-blind, randomised, placebo-controlled clinical trial for 15 days. Primary efficacy endpoint was the investigator assessed symptom score at the end of therapy (Major Symptom Score, MSSINV). RESULTS: Treatment with verum lead to a statistically significant, clinically relevant improvement of the symptom score (2.07 ± 0.18 [SEM] vs. 3.47 ± 0.28 score points, p = 0.0001; PP: N = 300) compared to placebo at visit 5. The Number Needed to Treat (NNT) was 7 (PP). Adverse events occurred in 9.8% of the patients treated with verum and 14.1% of the patients treated with placebo. No serious adverse event was observed. The investigators assessed the tolerability of the herbal drug combination predominantly as good and very good (96.4% verum, 95.3% placebo). CONCLUSION: The results prove the efficacy and tolerability of the herbal drug in the indication acute viral rhinosinusitis. Especially due to the favorable benefit-risk ratio the drug represents a suitable treatment alternative.

Herbal drug BNO 1016 is safe and effective in the treatment of acute viral rhinosinusitis.

CONCLUSION: Daily intake of 480 mg of BNO 1016 for 15 days is an effective treatment in acute viral rhinosinusitis. OBJECTIVES: The pooled efficacy data of two similar randomized placebo-controlled clinical trials were analyzed. Safety was evaluated on the basis of the individual trials. METHODS: The efficacy analysis was based on 589 patients. Treatment was performed orally with either 3 × 160 mg BNO 1016 (n = 294) or 3 × placebo (n = 295) for 15 days. In both trials patients underwent five visits to the investigational sites. Symptoms were evaluated according to the EPOS 2012 guideline. Ultrasonography was used to confirm the diagnosis at onset of treatment and the remission of symptoms at the last visit. Efficacy was evaluated by the investigator as the mean major symptom score (MSS) at the end of treatment (visit 5, day 14). Patients reported symptoms and social/emotional consequences of rhinosinusitis using a quality of life questionnaire (SNOT-20 GAV). RESULTS: MSS improved during the treatment period by a mean of 10.02 ± 1.61 score points to 2.47 ± 2.55 for BNO 1016 and of 9.87 ± 1.52 to 3.63 ± 3.63 for placebo. Differences between treatment groups at end of therapy (1.16 ± 3.14 score points; p < 0.0001) and patient-assessed quality of life (p = 0.0015) were statistically significant in favor of BNO 1016.

Cytokine inhibition after glucocorticoid exposure in healthy men with low versus high basal cortisol levels.

OBJECTIVE: The balance between glucocorticoid (GC) release and GC sensitivity in target cells is believed to be important to maintain homeostasis in the neuroendocrine control of inflammation. We investigated the impact of in vivo exposure to adrenocorticotropic hormone (ACTH) and dexamethasone (DEX) on GC sensitivity measured in vitro in healthy individuals with high versus low baseline cortisol levels. METHODS: 136 healthy male volunteers were screened twice and sorted according to their 24-hour urinary free cortisol (UFC) excretion. The 10 individuals with the highest UFC (290 +/- 87 nmol/24 h) and the 10 with the lowest UFC (168 +/- 34 nmol/24 h) were further tested. Measurements were performed at baseline, after a low dose (0.5 microg/1.73 m(2)) of ACTH challenge and after 2 weeks' exposure to DEX (0.1 mg twice daily). GC sensitivity was assessed in vitro as the ability of DEX to inhibit lipopolysaccharide-stimulated production of the cytokines interleukin 1-beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in a whole-blood assay. RESULTS: After exposure to DEX in vivo, inhibition of IL-6 and TNF-alpha decreased. Also, after DEX in vivo, low-cortisol men showed lower inhibition of IL-1beta and IL-6, both compared to the high-cortisol group and their own baseline levels. CONCLUSION: A downregulation of GC sensitivity in leukocytes after exposure to an exogenous GC seems to occur most strongly in men with low cortisol levels.

Effects of examination stress on psychological responses, sleep and allergic symptoms in atopic and non-atopic students.

BACKGROUND: Recent findings indicate that atopics may be more vulnerable to stress than non-atopics. However, the roles of psychological well-being and sleep in this presumed increased sensitivity are not known. PURPOSE: To investigate the effects of a brief naturalistic stressor on psychological responses, sleep, and allergic symptoms and to compare those responses between atopic and non-atopic individuals. METHODS: We assessed atopic and non-atopic students during a period without and during a period with examinations. RESULTS: For both atopic and non-atopic students, tension, anxiety, and depression deteriorated in response to examination, as did sleep latency and sleep quality. Overall, atopics were more tense, had more anxiety, longer sleep latencies, and were less well rested than non-atopics. Non-atopic students rose from bed later during the examination period. In response to examination, atopic students reported increased frequency of stress behaviors (e.g., eating fast), while decreased stress behaviors were reported by non-atopic students. Allergic symptoms were not affected. CONCLUSION: Atopic students were worse off in aspects of psychological well-being and sleep, but displayed only partly stronger responses to a stressor compared to non-atopic students. In spite of a broad negative response to examination, allergic symptoms were not affected.

Early timing of low-dose dexamethasone decreases inflammation in a murine model of eosinophilic airway disease.

CONCLUSION: A very low dose of dexamethasone (DEX) was as equally as sufficient as a pharmacological dose to decrease eosinophil inflammation in airways and bone marrow. The timing of DEX treatment in relation to allergen challenge was strongly decisive for the outcome of the inflammatory response. OBJECTIVES: We aimed to study compartmental allergic airway inflammatory responses to classic pharmacological and also extremely low physiological DEX dosage, given at different time points close to allergen challenge in a murine model. MATERIALS AND METHODS: Ovalbumin-sensitized BALB/c-mice were exposed to intra-nasal ovalbumin. DEX was given i.p. as 1 microg/kg low-dose or 500 microg/kg pharmacological single-dose 2 h before, immediately before or 7 h after each of three challenges. Inflammatory cells were evaluated in bronchoalveolar lavage (BAL), lungs, nasal mucosa, and bone marrow. RESULTS: Groups treated with low-dose DEX decreased eosinophilia in BAL to the same extent as the pharmacological dose, but only when administered before challenge. The most prominent decrease of eosinophils in BAL was seen in mice treated with the low dose 2 h before challenge. A similar response pattern as in BAL eosinophilia was detected in lung histopathology. DEX treatments had no obvious effects on inflammation in nasal mucosa.

Local treatment of cricoid cartilage defects with rhBMP-2 induces growth plate-like morphology of chondrogenesis.

OBJECTIVE: The ultrastructural characteristics of new bone and cartilage, induced at the site of cricoid cartilage defects treated with rhBMP-2 in rabbits, were investigated. STUDY DESIGN AND SETTING: A cricoid defect model was used. Fifteen rabbits were randomly and equally divided into 3 groups. Four rabbits from each group were treated with rhBMP-2, while one rabbit from each group was used as control. The rabbits were killed 1, 2, or 4 weeks after surgery. The healing pattern of the laryngeal wound was evaluated by light and transmission electron microscopy. RESULTS: Mineralized collagen type I matrix, osteoblasts, and osteoclast-like cells were present as early as 1 week after surgery. Well-structured bone trabeculas and growth plate-like structures were present 4 weeks after surgery. CONCLUSION: Intramembranous and endochondral osteogenesis take place at the site of cricoid cartilage defects treated with rhBMP-2. Progenitor cells of cricoid perichondrium form a growth plate-like structure similar to the epiphyseal growth plate. SIGNIFICANCE: This study reveals the pattern of BMP-2-induced repair of airway cartilage defects.

NF-kappaB mediated glucocorticoid response in the inner ear after acoustic trauma.

The inner ear of humans and experimental animals demonstrate an abundance of glucocorticoid receptors (GR). Glucocorticoids (GC) are widely used to treat different hearing disorders; yet the mechanisms of GC action on the inner ear are unknown. We demonstrate how GR can directly modulate hearing sensitivity in response to a moderate acoustic trauma that results in a hearing loss (10-30 dB). The GC agonist (dexamethasone) and the drugs (metyrapone + RU 486) showed opposing effects on hearing threshold shifts. GC agonist (dexamethasone) decreased the hearing threshold whereas pre-treatment with a GC synthesis inhibitor (metyrapone) in combination with a GR antagonist (RU 486) exacerbated auditory threshold shifts (25-60 dB) after acoustic trauma with statistically significant increase in GR mRNA and GR protein compared with the vehicle and acoustic trauma group. Acoustic trauma caused a significant increase in the nuclear transport of NF-kappaB, whereas pre-treatment with the drugs (metyrapone and RU 486) blocked NF-kappaB nuclear transport into spiral ganglion nuclei. An NF-kappaB inhibitor, pyrrolidine dithiocarbamate ammonium blocked the trauma-induced translocation of NF-kappaB and resulted in a hearing loss (45-60) dB. These results indicate that several factors define the responsiveness of the inner ear to GC, including the availability of ligand or receptor, and the nuclear translocation of GR and NF-kappaB. These findings will further our understanding of individual GC responsiveness to steroid treatment, and will help improve the development of pharmaceuticals to selectively target GR in the inner ear for individuals with increased sensitivity to acoustic trauma.

Cell origin in experimental repair of cricoid cartilage defects treated with recombinant human bone morphogenetic protein-2.

We determined the origin of new cartilage and new bone induced by recombinant human bone morphogenetic protein-2 (rhBMP-2) at the site of cricoid cartilage defects in rabbits randomly divided into eight groups. The cricoid cartilage was split vertically along the anterior midline and a strip was excised from the anterior part of the cricoid cartilage in all rabbits. The perichondrium from the anterior part of the cricoid cartilage was trimmed off in four groups; two groups treated with rhBMP-2 and two control groups. In four other groups, the anterior perichondrium was detached and used as a flap with two groups treated with rhBMP-2 and two groups serving as controls. The rabbits were killed 1 week or 4 weeks after surgery. The larynges were removed, fixed and sectioned, and the sections were stained for light microscopy using various cytochemical and immunological techniques. New cartilage was only present close to the host perichondrium adherent to cricoid cartilage in rabbits treated with rhBMP-2. New bone was present 4 weeks after surgery, although calcified matrix and alkaline phosphatase activity could be detected at the site of cricoid defects as early as 1 week after surgery. The cell proliferation marker Ki-67 was strongly expressed in granulation tissue and bone marrow, and it was moderately expressed in muscles adjacent to the cricoid cartilage in rhBMP-2-treated specimens. BMP receptors were strongly expressed in cartilage and moderately expressed in adjacent muscles. We conclude that new cartilage originates from the mesenchymal progenitor cells of host perichondrium adherent to cricoid cartilage in rabbits treated with rhBMP-2. New bone may originate from local muscle.

Effect of recombinant human BMP-2 on the repair of cricoid cartilage defects in young and adult rabbits: a comparative study.

OBJECTIVE: The study evaluated the possible differences in the repair of cricoid cartilage defects treated with recombinant human BMP-2 in young and adult rabbits. METHODS: A cricoid defect rabbit model was used. Thirty rabbits were randomly divided into eight groups. Two groups of young rabbits and two groups of adult rabbits were treated with rhBMP-2 delivered on an absorbable collagen sponge, while the other two groups of young rabbits and two groups of adult rabbits were used as controls. The rabbits were killed at 1 week or 4 weeks after surgery. A histomorphometric analysis and an evaluation of the expression of collagen types I, II, and X, and proliferating cell nuclear antigen as well as a study of distribution of calcified matrix, were performed. RESULTS: rhBMP-2 induced a marked chondrogenesis in both experimental age groups. However, in young rabbits the newly formed cartilage appeared more elongate, and the length of perichondrium involved was greater. The host cricoid cartilage of adult rabbits was calcified in large areas and displayed a strong matrix expression of collagen type X as well as collagen type I in the perichondrium, compared to the cricoid of young rabbits. In spite of these differences no immunohistochemical differences were found in the newly formed cartilage of both age groups treated with rhBMP-2. The cricoid cartilage defect was filled with new bone at 4 weeks in both age groups treated with rhBMP-2. New bone tissue had a well-defined trabecular structure. CONCLUSIONS: rhBMP-2 triggers appositional cartilage growth from the cricoid perichondrium of young rabbits more easily than from that of adult rabbits. The new bone induced by rhBMP-2 showed a similar immunohistochemical and morphological pattern in both age groups of rabbits.

Significance of endogenous glucocorticoid sensitivity for airway eosinophilia in a murine model of allergy.

CONCLUSIONS: Endogenous GC protects against allergic inflammatory responses in the airways. These effects are modulated by both peripheral blockade and inhibition of release. Individual response patterns to stress, i.e. corticosterone release and peripheral sensitivity, may influence both the central and peripheral levels of the allergic airway reaction in patients. OBJECTIVE: Glucocorticoids (GCs) modulate the allergic inflammatory response. Acute or chronic stress will influence circulating levels of GCs, rates of secretion, metabolism and target tissue sensitivity. In a clinical situation, stress may exacerbate or attenuate the asthmatic reaction. The aim of this study was to investigate the effects of inhibition of endogenous GC in an allergic airway inflammation model in the mouse. MATERIAL AND METHODS: An ovalbumin model using i.p. sensitization and intra-nasal challenge was used for respiratory eosinophilic inflammation. GC release was inhibited by administration of metyrapone (ME), and peripheral glucocorticoid receptors were blocked by administration of RU486 (RU). RESULTS: Inhibition with RU and ME increased eosinophilia in the bone marrow compared to controls (p < 0.05). Eosinophilia in bronchoalveolar lavage fluid increased in the sensitized groups compared to controls, but there were no differences between the sensitized groups. CD3+ and CD4+ cells were increased in the nasal mucosa as a result of treatment with RU and ME.

Sinusitis of odontogenic origin: pathophysiological implications of early treatment.

Although sinusitis is a common condition its pathogenesis is not clearly understood and there is lack of consensus concerning its treatment and prevention. Sinusitis is regarded as being primarily rhinogenous in origin, and oral/dental infections are considered to be predisposing factors. A review of the literature suggests that many cases of recurrent acute sinusitis are due to secondary rhinogenous bacterial colonization of antral mucosa that have been weakened and degenerated by chronic dental infection/inflammation. Unless the underlying dental condition, which may be asymptomatic or mildly symptomatic, is diagnosed and treated, the value of antibiotic treatment in such cases is questionable. In order to halt disease progression and avoid excessive antibiotic treatment, early intervention (both preventive and therapeutic) is necessary. Further research is required to establish the sequence of events by which infection of odontogenic origin initiates degenerative changes in the antral mucosa, culminating eventually in sinusitis.

Immune response to Mycoplasma pulmonis in nasal mucosa is modulated by the normal microbiota.

The impact of commensal bacteria on lymphocyte responses in the upper airways was studied in rat nasal mucosa after infection with the pathogen Mycoplasma pulmonis. Phenotyping was performed in situ by paired immunofluorescence staining in germ-free (GF) and conventional (CV) rats before and 3 wk after the monoinfection. Intraepithelial lymphocytes had expanded significantly in GF (P = 0.02) but not in CV rats. Furthermore, a striking proportional increase of T-cell receptor (TCR)alphabeta(+)CD4(+) cells was observed both in the lamina propria and epithelium of GF (P < 0.01) but not of CV rats. Notably, in contrast to the pre-infection state, both mucosal compartments showed a percentage of TCRalphabeta(+)CD4(+) cells that was significantly higher in GF (P = 0.03-P < 0.01) than in CV rats after the monoinfection. In parallel, both compartments displayed a percentage of TCRalphabeta(+) CD8(+) cells that was decreased in GF (P < 0.01) but not in CV rats. The small fraction of TCRgammadelta(+) T cells observed (< 5%) did not change quantitatively or phenotypically after infection. The size of organized nose-associated lymphoid tissue was, on average, increased 5.2-fold in GF rats versus 2.6-fold in CV rats. Collectively, our results demonstrated that the normal microbiota modulated markedly the nasal immune response elicited by monoinfection with M. pulmonis.

Recombinant human bone morphogenetic protein-2 enhances experimental laryngotracheal reconstruction in rabbits.

OBJECTIVE: Bone morphogenetic protein-2 offers potential benefits for cartilage regeneration. We investigated the effect of recombinant human bone morphogenetic protein-2 (rhBMP-2) on the regeneration of laryngeal cartilage and respiratory epithelium in a rabbit model. MATERIAL AND METHODS: We used a cricoid defect rabbit model. Twenty-four rabbits were randomly divided into four equal groups. Two groups were treated with 5 microg of rhBMP-2 delivered on an absorbable collagen sponge and the other two groups were used as controls. One group of treated rabbits and one group of control rabbits were euthanized 1 week after surgery, while the others were euthanized 4 weeks after surgery. The healing pattern of the laryngeal wound was evaluated by means of histomorphometry. RESULTS: Regeneration of both the epithelial layer and cartilage was significantly better in rabbits treated with rhBMP-2. Four weeks after surgery, the cricoid cartilage defect was completely repaired by new cartilage and new bone in rabbits treated with rhBMP-2. Furthermore, the lining respiratory epithelium healed more rapidly in treated rabbits. CONCLUSION: rhBMP-2, delivered via an absorbable collagen sponge, induces complete regeneration and repair of rabbit cricoid cartilage defects. It also induces faster relining and regeneration of airway epithelium than in control rabbits.

Structural characteristics of repair tissue of cricoid cartilage defects treated with recombinant human bone morphogenetic protein-2.

We examined the structural characteristics of repair tissue induced by recombinant human bone morphogenetic protein-2 in a rabbit model of laryngotracheal reconstruction. Twenty-four New Zealand White rabbits were randomly divided into four groups of six rabbits. Two groups were treated with recombinant human bone morphogenetic protein-2 delivered on an absorbable collagen sponge, while two groups were used as controls. Rabbits were euthanized at 1 and 4 weeks after surgery. The larynx was removed, fixed, and sectioned. The sections were stained with hematoxylin-eosin, safranine O/fast green, and immunostained with an antibody for tissue inhibitor of metalloproteinases-1. In rabbits treated with bone morphogenetic protein-2, the defects were filled with new cartilage and bone at 4 weeks after surgery. There were no discontinuities or gaps at the margins of the cartilage defects. Proteoglycans were synthesized in new cartilage in rabbits treated with bone morphogenetic protein-2, and were present 4 weeks after surgery. The general aspects of the vascular pattern and the pattern of tissue inhibitor of metalloproteinases-1 expression were similar in control and treated rabbits, both 1 week and 4 weeks after surgery. The repair tissue induced by recombinant human bone morphogenetic protein-2 consisted of new cartilage and bone perfectly integrated with host tissue at the site of the cricoid cartilage defects. This new cartilage was able to mature and produce proteoglycans.

ME-609: a treatment for recurrent herpes simplex virus infections.

Studies in conventional murine models of HSV infection use immunologically naive animals. These models thus mimic primary infections rather than recurrent infections in humans. We have, therefore, used a newly developed mouse model that more closely mimics recurrent HSV infection in humans. In this model, the mice are infected, and zosteriform HSV-1 infection develops in the presence of a primed immune response using adoptive transfer of immunity (ATI) as we have described previously. Using the ATI mouse model, it has been shown that a more beneficial therapy for recurrent mucocutaneous HSV infection could be achieved by controlling both the viral replication and the inflammatory response to the virus. Topical treatment was initiated in this model at the time of first occurrence of symptoms and was given three times daily for 4 days. Topical treatment with ME-609 (which contains 5% acyclovir and 1% hydrocortisone) in the ATI mouse model was substantially more efficacious than 5% Zovirax cream, 1% hydrocortisone or no treatment, respectively. The beneficial properties of ME-609 were also found to be superior to those of Zovirax cream when tested in the standard guinea pig model, representing a primary HSV infection. ME-609 represents a novel treatment principle of recurrent HSV infections and the present paper summarizes the preclinical and early clinical experience of ME-609.

Nasal polyps in cystic fibrosis: clinical endoscopic study with nasal lavage fluid analysis.

STUDY OBJECTIVES: Nasal polyps frequently appear in patients with cystic fibrosis (CF). The aims of this study were to focus on what problems (symptoms, endoscopic findings, and laboratory correlates) nasal polyps cause the CF patient, and how these correlate to the total health situation of this patient group. PATIENTS AND STUDY DESIGN: The clinical histories, endoscopic investigations of the nasal cavity, and analyses of nasal lavage fluid of 44 patients with CF complicated with nasal polyposis have been compared with those of 67 CF control subjects. The patients were examined at annual control examinations (with pulmonary tests, working capacity, liver tests, and bacterial and blood tests) from 1995 to 1996 at Stockholm Cystic Fibrosis Center, Huddinge University Hospital. All patients were > 2 years of age. The endoscopic findings were related to the actual pulmonary function, inflammatory blood parameters, colonizing pathogens, antibodies (Staphylococcus aureus and Pseudomonas aeruginosa), and genotype. RESULTS: The patients with nasal polyps differed with respect to chronic colonization of P aeruginosa in sputum samples and had a higher occurrence of serum antibodies against the same species. The two groups did not differ in pulmonary functions, inflammatory parameters, or genotype. The polyps found were mainly small (within the meatus media) and gave no significant increase in ongoing clinical symptoms such as rhinorrhea, nasal obstruction, or hyposmia. Neither was any significantly marked finding concerning the nose (mucosal swellings, secretion, etc.) made in the polyp patients. The patients with CF scored slightly lower in a smell identification test in comparison with the healthy control group. The nasal lavage fluid was analyzed (in 93 of the 111 patients) for the occurrence of P aeruginosa (by polymerase-chain reaction [PCR]), interleukin [IL]-5, IL-8, and lysozyme. The lysozyme and IL-8 content was equal in the two CF groups but increased in comparison with the healthy control group. P aeruginosa was not detected with PCR in any nasal lavage fluid. No measurable levels of IL-5 in the nasal lavage were found. CONCLUSIONS: There was a higher frequency of chronic colonization of P aeruginosa in the lower respiratory tract in patients with nasal polyps. Otherwise, nonsevere nasal polyposis was not an indicator of lower respiratory tract morbidity in CF patients.