Influence of terbutaline on natural killer cell activity

Studies on the effect of cAMP-inducing agents on NK activity have been contradictory. The aim of this study was to investigate the acute effects of beta-agonists on NK activity in vivo in 15 asthmatics and 3 healthy volunteers. Blood samples of NK activity were taken at regular intervals after placebo and after subcutaneous injection of 7 micrograms/kg of terbutaline. NK activity was measured by the standard 4-h Chromium51 release assay against the leukemic line K 562 at a 50:1 effector/target cell ratio. Compared with placebo, terbutaline induced within 30-60 min a significant increase in NK activity which lasted less than 2 h. Further studies are necessary to investigate the effect of long-term beta-agonist treatment on NK activity.     

The common cold: Effects of intranasal fluticasone propionate treatment

Objective: A double-blind, randomized, placebo-controlled trial was conducted to study the effect of the intranasal corticosteroid, fluticasone propionate (FP), in the naturally occurring common cold. Methods: One hundred ninety-nine young adults received high-dose FP (200 μg four times daily) or placebo beginning 24 to 48 hours after onset of the common cold for 6 days. All symptoms were recorded on diary cards on days 1 to 20, and clinical examinations were carried out on days 1, 7, and 21. Nasopharyngeal aspirates were collected on days 1 and 7 for detection of rhinoviruses (found in 105 subjects) and Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis (found in 52 subjects) in the nasopharynx. Results: In general, FP treatment had no clinically recognizable effects on the symptoms of the common cold, although it significantly reduced nasal congestion and cough on some study days. After treatment, rhinoviruses were cultured more often in the FP treatment group (37% vs 14%, p < 0.001), but this had no effect on the symptoms of common cold. FP treatment produced no changes in the colonization of pathogenic bacteria in the nasopharynx. Some symptoms of common cold were significantly more severe during days 1 to 10 (p < 0.05) in subjects found to have positive cultures for S. pneumoniae, H. influenzae, or M. catarrhalis in the nasopharynx on day 1 (n = 33). Conclusion: FP treatment does not have any marked effects on the symptoms of the common cold. FP treatment induced prolonged shedding of viable rhinoviruses. Some symptoms of the common cold were significantly more severe in subjects with pathogenic bacteria in the nasopharynx. (J Allergy Clin Immunol 1998;101:726–31.)     

Effects of fluticasone propionate and beclomethasone dipropionate on parameters of inflammation in peripheral blood of patients with asthma

Bronchial inflammation plays a central role in asthma. We investigated whether parameters of inflammation were increased in peripheral blood. Furthermore, we tested whether fluticasone propionate (FP), a new inhaled corticosteroid (ICS), and beclomethasone dipropionate (BDP) affected these parameters. FP 750 μg/day and BDP 1500 μg/day were compared in a randomized, crossover study consisting of two 6-week treatment periods, each preceded by a 3-week placebo period. Twenty-one patients with symptomatic asthma completed the study. The results were compared with those of six normal subjects (controls). Immunophenotyping of inflammatory cells was performed in whole blood, and serum eosinophil cationic protein (ECP) was measured. With regard to clinical efficacy, ICS increased PCjo histamine by more than 1.9 doubling doses and FEV, by more than 0.34 1. The number of CD3/HLA-DR+ lymphocytes was significantly increased in asthmatics compared to the normal subjects, both after placebo (P<0.01) and after therapy (P<0.05). The CD3/HLA-DR-H lymphocytes decreased significantly after treatment with FP (P<0.05). Serum ECP was elevated in patients without ICS and decreased after treatment with BDP (P<0.001). In conclusion, the number of CD3/HLA-DR-I- lymphocytes and serum ECP levels were raised in the peripheral blood of symptomatic asthmatics, and decreased by clinically effective doses of ICS. In this respect, FP 750 ng/day was at least as effective as BDP 1500 μg/day.     

Motivational syndromes associated with natural killer cell activity

This article reports three studies that taken together support two hypotheses: (a) that the stressed power motivation syndrome is associated with relatively low natural killer cell activity (NKCA) and (b) that the unstressed affiliation motivation syndrome is associated with higher NKCA. In Study 1, college students who were relatively high in stressed power motivation had significantly lower NKCA than did their peers. In addition, students high in unstressed affiliation motivation had significantly greater NKCA than did those showing less evidence of this syndrome. Study 2 replicated these findings on a sample of middle-class men. In Study 3, which tested the hypotheses among adult patients from a Health Maintenance Organization, results were in the same direction but less significant. Meta-analyses clearly indicate that the combined evidence from the three studies reliably supports both hypotheses.This work was supported in part by Grant CA-29155 from the National Cancer Institute, Grant MH-1589 from the National Institute of Mental Health, Grant RR-01032 from the National Institutes of Health General Clinical Research Centers Program of the Division of Research Resources, Biomedical Research Support Grant RR-5487 (University Hospital), and a grant from the John D. and Catherine T. MacArthur Foundation. Additional support was provided under the Office of Naval Research Contract N-00014-79-C-1068 with funds of the Naval Medical Research and Developmental Command. The opinions or assertions contained herein are those of the authors and are not to be construed as official or reflecting the views of the Navy Department or Naval Service at large.     

Effect of montelukast compared with inhaled fluticasone on airway inflammation

BACKGROUND: Inhaled corticosteroids are currently regarded as the gold standard in anti-inflammatory therapy, however, leukotriene receptor antagonists have been ascribed anti-inflammatory properties. OBJECTIVE: We directly compared the anti-inflammatory effects of inhaled fluticasone propionate (FP, 100 microg Diskus, twice daily) and oral montelukast (MON 10 mg, nocte) in bronchial biopsies of patients with asthma in a double-blind, double-dummy, parallel-group design. METHODS: Bronchial biopsies, serum and urine samples were collected from 36 atopic asthmatics before and after 8 weeks of treatment. Activated T cells (CD25+), eosinophils (MBP+) and mast cells (tryptase+) were analysed by immunohistochemistry. Serum eosinophil cationic protein (ECP) and IL-5 were analysed by radio and enzyme immunoassay (EIA), respectively. Urinary 9alpha-11beta-PGF2 and leukotriene E4 (LTE4) were measured by EIA. RESULTS: A comparison of changes from baseline [FP/MON ratio (95% confidence interval)] of activated T cells was not different when subjects were treated with FP compared to treatment with MON [1.00 (0.18-4.86); P=0.924]. Following treatment, mast cells in the FP group were significantly lower than in the group treated with MON [0.39 (0.16-0.97); P=0.041]. There was no difference in the number of eosinophils in the lamina propria following either treatment [0.54 (0.05-2.57); P=0.263]. However, treatment with FP resulted in a significantly greater decrease in serum ECP, compared to treatment with MON [0.37 (0.25-0.71); P=0.002]. CONCLUSIONS: FP appears to be superior to MON as an anti-inflammatory therapy in mild asthmatics.     

Effects of low doses of inhaled fluticasone propionate on inflammation and remodelling in persistent-mild asthma

In asthma a dysregulation of eosinophil apoptosis and an imbalance of metalloproteinase-9 (MMP-9) and tissue inhibitor metalloproteinase-1 (TIMP-1) play an important role in airway inflammation and remodelling. We evaluated the effects of a low dose of inhaled fluticasone proprionate (FP) (100 microg bid by Diskus) for 4 weeks in 24 steroid naive patients with mild persistent asthma, symptomatic and with a sputum eosinophilia >or=3% on clinical outcomes and inflammatory markers such as the induced sputum eosinophils, the induced sputum apoptotic eosinophils, the levels of MMP-9 and TIMP-1 and their molar ratio in the induced sputum supernatants. After FP treatment forced expiratory volume (FEV1) and FEV1/forced vital capacity values, PEF (L/min), sputum apoptotic eosinophils, and MMP-9/TIMP-1 molar ratio in sputum supernatants of asthmatic subjects were significantly increased in comparison with baseline, while sputum eosinophils significantly decreased. Change (Delta) in FEV1 after treatment with FP negatively correlated with the Delta in sputum eosinophils, while the Delta in MMP-9 values positively correlated with Delta in TIMP-1 values. This study shows that the clinical improvement achieved by the use of low doses of FP in asthmatics is related, at least in part, to the resolution of eosinophilic inflammation and the downregulation of remodelling markers.     

Subsets of human natural killer cells and their regulatory effects

Human natural killer (NK) cells have distinct functions as NK^tolerant, NK^cytotoxic and NK^regulatory cells and can be divided into different subsets based on the relative expression of the surface markers CD27 and CD11b. CD27⁺ NK cells, which are abundant cytokine producers, are numerically in the minority in human peripheral blood but constitute the large population of NK cells in cord blood, spleen, tonsil and decidua tissues. Recent data suggest that these NK cells may have immunoregulatory properties under certain conditions. In this review, we will focus on these new NK cell subsets and discuss how regulatory NK cells may serve as rheostats or sentinels in controlling inflammation and maintaining immune homeostasis in various organs.     

A double-blind, placebo-controlled comparison of treatment with fluticasone propionate and levocabastine in patients with seasonal allergic rhinitis. FLNCO2 Italian Study Group

Fluticasone propionate aqueous nasal spray (FPANS) is a topically active glucocorticoid which has been successfully used for the treatment of seasonal allergic rhinitis (SAR). Topical levocabastine is a highly selective H1 antagonist which has been proposed as an alternative treatment of SAR. The purpose of this study was to compare the clinical efficacy of two topical nasal treatments, FPANS and levocabastine, in the treatment of SAR. Additionally, the effect of treatments on nasal inflammation was examined during natural pollen exposure. A group of 288 adolescent and adult patients with at least a 2-year history of SAR to seasonal pollens participated in a multicenter, doubleblind, double-dummy, and placebo-controlled study. Patients were treated with either FPANS 200 microg, once daily (n = 97), or topical levocabastine, 200 microg, given twice daily (n = 96), or matched placebo (n = 95) for a period of 6 weeks, starting from the expected beginning of the pollen season. Clinically relevant pollens included Parietaria, olive, and grass. Assessment of efficacy was based on scores of daily nasal symptoms and on nasal cytology of nasal lavage. Nasal lavage was performed immediately before, during, and at the end of treatment in 39 patients. FPANS significantly increased the percentage of symptom-free days for nasal obstruction on waking and during the day, rhinorrhea, sneezing, and itching. FPANS provided a better control for night and day nasal obstruction (P<0.02 and P<0.01) and rhinorrhea (P<0.01) than levocabas tine. In addition, fewer patients treated with FPANS used rescue medication (P<0.025). The percentage of eosinophils in nasal lavage was reduced only during treatment with FPANS. The results of this study indicate that FPANS 200 microg, once daily, provides a better clinical effect than levocabastine 200 microg, twice daily, in patients with SAR. Unlike levocabastine, FPANS significantly attenuates nasal eosinophilia during pollen exposure, a feature which may explain its therapeutic efficacy.     

Preconception peripheral natural killer cell activity as a predictor of pregnancy outcome in patients with unexplained infertility

PROBLEM: Preconception high peripheral natural killer (NK) cell activity in women with recurrent spontaneous abortion can predict subsequent miscarriages. We have examined prospectively, for the first time, the pregnancy rate in patients with unexplained infertility by measuring the peripheral NK activity. METHOD OF STUDY: We tested the peripheral NK activity of 94 infertile women who despite treatment were unable to conceive for 6 or more months (mean; 2.4 years). Peripheral NK activity was measured by a chromium-51 release cytotoxicity assay. Women were followed for 2 years and assessed. RESULTS: In 77 patients who were followed for 2 years, 28 had conceived but 49 did not. The peripheral NK activity of the group that became pregnant (mean +/- S.D.; 34.5 +/- 13.8%) was significantly lower than that of non-conception group (42.3 +/- 13.3%, P = 0.017). CONCLUSIONS: Our finding suggests that elevated peripheral NK activity in patients with unexplained infertility is a risk factor for attaining pregnancy success.     

Effect of intranasal fluticasone propionate and triamcinolone acetonide on basal and dynamic measures of hypothalamic–pituitary–adrenal-axis activity in healthy volunteers

BACKGROUND : Most published studies show that intranasal corticosteroids have no effect on the hypothalamic-pituitary-adrenal (HPA) axis, but there have been isolated reports to the contrary, contradicting accumulated knowledge on pharmacokinetics. OBJECTIVE : To re-evaluate the effect of fluticasone propionate aqueous nasal spray (FPANS) and triamcinolone acetonide (TAA) aqueous nasal spray on the HPA axis using an improved study design. METHODS : Twenty-three healthy volunteers were randomized in a double-blind, three-way crossover study. The study comprised a 4-day placebo run-in phase followed by three 4-day treatment periods (placebo, FPANS (200 microg once daily) or TAA aqueous nasal spray (220 microg once daily)), separated by 7-14 days washout intervals. Before the first, and on the last day of each treatment period, 12-h overnight urine was collected to assess cortisol excretion and cortisol creatinine ratio. Approximately 26 h after the last administration of study medication, volunteers underwent stimulation with 0.5 microg adrenocorticotropic hormone (ACTH). Serum cortisol concentrations were measured before and 20 and 30 min after injection. Blood and urine samples were analysed for cortisol by liquid chromatography tandem mass spectrometry. RESULTS : Compared with placebo, EP or TAA had no significant effect on mean overnight (12 h) urinary cortisol excretion, and did not significantly suppress the overnight geometric mean urinary cortisol/creatinine excretion ratio. Values for serum cortisol before and after ACTH simulation showed no significant suppression, although there was a slight blunting of the HPA-axis response following TAA treatment. CONCLUSION : This study confirms that there are no detectable effects on the HPA axis following short-term intranasal FP or TAA at their recommended dosages.     

Cells with natural killer activity in human rabies.

Cytotoxic lymphocyte function in 13 patients with rabies was studied by counting the number of CD56 cells and assessing natural killer (NK) cell activity. There was no significant difference in the number of killer cells between rabies patients and 31 normal controls (P greater than 0.05). Two of six non-fatal encephalitic patients due to causes other than rabies had reduced CD56 numbers. Base-line NK cell responses versus K562 cell targets did not differ among the normal control and rabies groups (P greater than 0.05). Study of the non-rabies encephalitis group showed heterogeneous results with wide variation. Significant enhancement of NK activity was seen in four rabies patients and in 10 normal control subjects tested after interferon-alpha (IFN-alpha) and IL-2. None of the four patients with encephalitis due to causes other than rabies showed such enhancement. Our results suggest that NK cells of rabies patients are not fully stimulated and that this might contribute to the virulence of rabies. The cause of this phenomenon remains unknown.     

Asbestos fibres inhibit the in vitro activity of lymphokine-activated killer (LAK) cells from healthy individuals and patients with malignant mesothelioma.

Asbestos exposure is associated with an increased incidence of several malignancies, including malignant mesothelioma (MM). This study evaluates the relationship between asbestos exposure and the in vitro generation and function of LAK cells, an immune effector cell population with powerful lytic activity against MM cells. Both serpentine (chrysotile) and amphibole (amosite and crocidolite) forms of asbestos fibres suppress LAK cell generation, viability (by 5-11%, P less than 0.02) and cell recovery (by 13-15%, P less than 0.02). However, the LAK cells generated in the presence of the amphiboles were as effective as unexposed cells in lysing both standard tumour cell targets (K562, 56.4% lysis versus 61.5%, respectively, P greater than 0.5; NS; Daudi, 60.5% lysis versus 64.5% P greater than 0.5; NS), and MM tumour cell targets (mean of three MM cell lines 48.3% versus 46.3%, P greater than 0.5; NS), whereas the function of LAK cells generated in the presence of chrysotile was significantly reduced against three out of the five tumour cell targets tested (P less than 0.03). In the presence of asbestos fibres, LAK cell function was reduced against all five tumour cell targets (P less than 0.01), irrespective of whether the cell donors were healthy individuals or patients with MM. NK cell activity was also suppressed (P less than 0.01). The serpentine form of asbestos, chrysotile, was significantly more suppressive of both effector cell functions than either of the amphiboles (P less than 0.01). These findings suggest that asbestos exposure may suppress the function and in some instances the generation of immune effector cell mechanisms, thereby increasing the risk of disease and malignancy.     

Presence of fluticasone propionate on human nasal mucosal surface and in human nasal tissue over a period of 24 h after intranasal application

BACKGROUND: Once-daily use of nasally applied glucocorticoids was demonstrated to be effective in the treatment of allergic rhinitis. The aim of the study was to measure concentrations of fluticasone propionate (FP) in nasal secretion and nasal tissue over a period of 1 day after a single application of 100 microg FP. METHODS: Twenty-six patients applied nasal FP spray at different time intervals before surgery. Cotton swabs, used to clean the mucosal surface, and resected nasal tissue were extracted. FP concentrations were determined by RIA. RESULTS: FP was found in nasal secretions in concentrations from 15 to 1 microg/g over a period of 20 h, and in nasal tissue in concentrations from 200 to 13 ng/g up to 24 h after the single application. CONCLUSION: The long-persisting high concentrations of FP provide the pharmacokinetic basis for once-daily treatment.     

Differential loss of natural killer cell activity in patients with acute myocardial infarction and stable angina pectoris

Background: To evaluate the activity of natural killer cells through their inhibitory and activating receptors and quantity in peripheral blood mononuclear cells extracted from patients with acute myocardial infarction, stable angina pectoris and the controls. Methods: 100 patients with myocardial infarction, 100 with stable angina, and 20 healthy volunteers were recruited into the study. 20 randomly chosen people per group were examined for the whole human genome microarray analysis to detect the gene expressions of all 40 inhibitory and activating natural killer cell receptors. Flow cytometry analysis was applied to all 200 patients to measure the quantity of natural killer cells. Results: In myocardial infarction group, the mRNA expressions of six inhibitory receptors KIR2DL2, KIR3DL3, CD94, NKG2A, KLRB1, KLRG1, and eight activating receptors KIR2DS3, KIR2DS5, NKp30, NTB-A, CRACC, CD2, CD7 and CD96 were significantly down-regulated (P<0.05) compared with both angina patients and the controls. There was no statistical difference in receptor expressions between angina patients and control group. The quantity of natural killer cells was significantly decreased in both infarction and angina patients compared with normal range (P<0.001). Conclusions: The significant mRNAs down-regulation of several receptors in myocardial infarction group and reduction in the quantity of natural killer cells in both myocardial infarction and angina patients showed a quantitative loss and dysfunction of natural killer cells in myocardial infarction patients.     

Immunity and depression: Insomnia,Retardation, and reduction of natural killer cell activity

Depressed patients show a reduction of natural killer (NK) cell activity which may be associated with specific depressive symptoms. The present study demonstrated that sleep disturbance and retardation, but not other depressive symptoms, were negatively correlated with NK activity in 38 depressed patients. Specific behavioral changes in depression such as sleep disturbance and retardation were found to predict 16% of the variance of cytotoxicity levels in depression.     

MP‐AzeFlu is more effective than fluticasone propionate for the treatment of allergic rhinitis in children

The objective was to evaluate the efficacy of MP‐AzeFlu (Dymista^®) vs fluticasone propionate (FP), (both 1 spray/nostril bid), in children with allergic rhinitis (AR). MP‐AzeFlu combines azelastine hydrochloride, FP and a novel formulation in a single spray. Children were randomized in a 3 : 1 ratio to MP‐AzeFlu or FP in this open‐label, 3‐month study. Efficacy was assessed in children aged ≥ 6 to <12 years (MP‐AzeFlu: n = 264; FP: n = 89), using a 4‐point symptom severity rating scale from 0 to 3 (0 = no symptoms; 3 = severe symptoms). Over the 3‐month period, MP‐AzeFlu‐treated children experienced significantly greater symptom relief than FP‐treated children (Diff: ?0.14; 95% CI: ?0.28, ?0.01; P = 0.04), noted from the first day (particularly the first 7 days) and sustained for 90 days. More MP‐AzeFlu children achieved symptom‐free or mild symptom severity status, and did so up to 16 days faster than FP. MP‐AzeFlu provides significantly greater, more rapid and clinically relevant symptom relief than FP in children with AR.     

Long-term study of fluticasone propionate aqueous nasal spray in acute and maintenance therapy of nasal polyposis

Background: Topical steroids are first‐line medication to control nasal polyposis (NP), a disease with long‐term clinical course. Objective: The aim of this study was to evaluate the efficacy and safety of fluticasone propionate aqueous nasal spray (FPANS) 200 μg twice a day (bd) after 1 month of treatment, and to compare FPANS 200 μg bd and FPANS 200 μg once a day (od) in maintenance and long‐term treatment. Methods: Double‐blind, placebo‐controlled, 8‐month study with three treatment periods (1‐month acute period followed with 1‐month maintenance period and 6‐month follow‐up period) was carried out. Group 1 received FPANS 200 μg bd, during acute, maintenance and follow‐up periods, Group 2 received FPANS 200 μg bd during acute period and FPANS 200 μg od during maintenance and follow‐up periods, and Group 3 received placebo during acute and maintenance periods and FPANS 200 μg bd during follow‐up period. Endpoints were change from baseline in clinic peak nasal inspiratory flow (PNIF), domiciliary evening PNIF, intensity of symptoms and polyposis grade. Results: After acute period and maintenance periods, FPANS 200 μg bd was significantly more effective than placebo on all endpoints and more effective than FPANS 200 μg od after 1‐month maintenance period on clinic PNIF, evening PNIF, obstruction, percentage of days with no sense of smell and percentage of nights with no disturbances. The two doses were similar on other endpoints. After the 6‐month follow‐up period, there was no difference between the two doses of FPANS at all efficacy endpoints. The safety profile of FPANS did not highlight any new or unanticipated adverse events. Conclusion: The study demonstrated the efficacy of FPANS 200 μg bd in acute treatment and FPANS 200 μg od as a sufficient dose to maintain a long‐term efficacy in the treatment for NP.     

Suppression of natural killer cell activity by splenocyte transplantation in a rat model of endometriosis

BACKGROUND: One immune characteristic of endometriosis is a decrease in natural killer (NK) cell activity. This study was performed to determine whether an abnormal immune reaction in an endometriosis animal model could be transferred to an animal of the same species. METHODS: An endometriosis model was prepared using 8 week old female rats by grafting a small section of one uterine horn onto the mesentery, followed 4 weeks later by removal of the spleen and remaining uterine horn. Splenocytes, that had been depleted of macrophages were injected via the tail vein, and NK cell activity of splenocytes was determined 4 days later. The uterus was simultaneously investigated immunohistochemically for immune cells. There was a control group (untreated; group 1), a control-splenocyte injection group (group 2), an experimental endometriosis model group (group 3) and an endometriosis model splenocyte injection group (group 4). RESULTS: Splenocyte NK cell activity was decreased in group 3 to 42.0% of that of group 1 and in group 4 to 38.9%. Immunohistologically, the number of NK cells in groups 3 and 4 markedly decreased to 62.0 and 55.1% of group 1 respectively. CONCLUSION: It was demonstrated that abnormal immunity caused by allograft of immune cells could recur in an endometriosis rat model.     

No difference in natural killer or natural killer T-cell population, but aberrant T-helper cell population in the endometrium of women with repeated miscarriage

BACKGROUND: The aim of this study was to assess the natural killer (NK) cell and natural killer T (NKT) cell populations and cytokine expression of T-helper (Th) cells in the endometrium of women who suffered from unexplained repeated miscarriage (RM). METHODS: The percentages of NK cells, NKT cells and CD4(+) cells expressing intracellular interferon (IFN)-gamma, interleukin (IL)-4 and tumour necrosis factor (TNF)-alpha were measured by flow cytometry in the endometrium of 20 RM women and 17 fertile control women in the mid-luteal phase of the menstrual cycle. RESULTS: No significant differences in CD56(+) NK cell or CD3(+)CD4(-)CD8(-)Valpha24(+)Vbeta11(+) NKT cell percentages were found between RM and control women. However, in RM women compared with control women, the percentages of CD3(+) cells (mean 40.3 versus 56.5%), CD4(+)IFN-gamma(+) cells (28.4 versus 39.5%) and CD4(+)TNF-alpha(+) cells (32.9 versus 45.8%) were significantly lower. The Th1/Th2 cell balance in RM women did not differ from that of controls. CONCLUSIONS: Immunodystrophism detected as diminution of the Th cell population rather than Th1 predominance, NK cell or NKT cell accentuation in the endometrium might underlie the pathophysiology of unexplained RM. This finding provokes an additional controversy on the Th1/Th2 balance concerning RM aetiology.