Maciej Ciebiada

Montelukast with desloratadine or levocetirizine for the treatment of persistent allergic rhinitis

BACKGROUND Montelukast sodium is approved as a treatment for intermittent and persistent allergic rhinitis (AR), but it has not been evaluated as combined therapy with antihistamines for persistent AR. OBJECTIVE To investigate the effects of 6 weeks of treatment of persistent AR with desloratadine, levocetirizine, or montelukast alone or in combination. METHODS A randomized, double-blind, placebo-controlled crossover study was performed. Patients were assigned to 2 arms: 20 received montelukast, 10 mg/d, desloratadine, 5 mg/d, or both or placebo and 20 received montelukast, levocetirizine, or both, 5 mg/d, or placebo. The treatment periods were separated by 2-week washout periods. Symptom scoring, skin prick tests, spirometry, rhinometry, and nasal lavage were performed the day before and the last days of the treatment periods. Eosinophil cationic protein levels were evaluated by means of nasal lavage. RESULTS The mean +/- SD total baseline nasal symptom score was 7.7 +/- 0.49 before treatment, 3.74 +/- 0.54 after desloratadine use, 3.6 +/- 0.48 after montelukast use, and 3.04 +/- 0.4 after montelukast-desloratadine use. The mean +/- SD baseline nasal symptom score was 7.95 +/- 0.68 before treatment, 3.02 +/- 0.64 after levocetirizine use, 3.44 +/- 0.55 after montelukast use, and 2.14 +/- 0.39 after montelukast-levocetirizine use. The greatest improvement in nasal symptoms occurred after combination treatment. Decreases in the level of eosinophil cationic protein were greater after the combined use of montelukast and antihistamine than after each agent given alone. CONCLUSIONS For persistent AR, the combination of montelukast and either desloratadine or levocetirizine is more effective than monotherapy with these agents.

Exhaled eicosanoids and biomarkers of oxidative stress in exacerbation of chronic obstructive pulmonary disease.

Introduction Eicosanoids and oxidants play an important role in inflammation, but their role in chronic obstructive pulmonary disease (COPD) is uncertain. In this study we hypothesized that levels of exhaled leukotrienes, prostaglandins and biomarkers of oxidative stress are increased in infectious exacerbations of COPD and that they decrease after antibiotic therapy. Material and methods Cysteinyl-leukotrienes (LTs), leukotriene B4 (LTB4), prostaglandin E4, hydrogen peroxide (H2O2) and 8-isoprostane were measured in exhaled breath condensate (EBC) in 16 COPD patients with infectious exacerbations (mean age 64 ±12 years, 13 male) on day 1, during antibiotic therapy (days 2-4), 2-4 days after therapy and at a follow-up visit when stable (21-28 days after therapy). Results There was a significant fall in concentration of cys-LTs, LTB4 and 8-isoprostane at visit 3 compared to day 1 (cys-LTs: 196.5 ±38.4 pg/ml vs. 50.1 ±8.2 pg/ml, p < 0.002; LTB4: 153.6 ±25.5 pg/ml vs. 71.9 ±11.3 pg/ml, p < 0.05; 8-isoprostane: 121.4 ±14.6 pg/ml vs. 56.1 ±5.2 pg/ml, p < 0.03, respectively). Exhaled H2O2 was higher on day 1 compared to that at visits 2 and 3 (0.74 ±0.046 µM vs. 0.52 ±0.028 µM and 0.35 ±0.029 µM, p < 0.01 and p < 0.01, respectively). Exhaled PGE2 levels did not change during exacerbations of COPD. Exhaled eicosanoids and H2O2 in EBC measured at the follow-up visit (stable COPD) were significantly higher compared to those from healthy subjects. Conclusions We conclude that eicosanoids and oxidants are increased in infectious exacerbations of COPD. They are also elevated in the airways of stable COPD patients compared to healthy subjects.

Intercellular adhesion molecule 1 and tumor necrosis factor α in asthma and persistent allergic rhinitis: relationship with disease severity

BACKGROUND Tumor necrosis factor alpha (TNF-alpha) is involved in the up-regulation of intercellular adhesion molecule 1 (ICAM-1). Allergic rhinitis is often associated with bronchial hyperresponsiveness. OBJECTIVE We investigated the relationship between allergic airway disease severity and serum concentrations of soluble ICAM-1 (sICAM-1) and TNF-alpha and nasal expression of ICAM-1. METHODS Serum concentrations of TNF-alpha and sICAM-1 were investigated in 85 adults with persistent rhinitis and 90 patients with asthma. Seventy patients with rhinitis were challenged with methacholine. Nasal biopsy for ICAM-1 expression was performed in 6 patients with moderate-severe rhinitis and in 6 patients with mild rhinitis. RESULTS In patients with rhinitis, serum sICAM-1 concentrations were as follows: group without bronchial hyperresponsiveness (n = 29), 206.85 ng/mL; group with bronchial hyperresponsiveness but without asthma symptoms (n = 20), 233.39 ng/mL; and group with newly recognized asthma (n = 21), 260.06 ng/mL. The sICAM-1 level was significantly lower in patients with mild rhinitis (216.21 ng/mL) than in patients with moderate-severe rhinitis (244.08 ng/mL). Nasal ICAM-1 expression was significantly higher in the moderate-severe rhinitis group than in the mild rhinitis group. In patients with asthma, serum concentrations of sICAM-1 were as follows: patients with mild asthma, 272.8 ng/mL; patients with moderate asthma, 340.16 ng/mL; patients with severe asthma without oral corticosteroids therapy, 426.74 ng/mL; and patients with severe asthma with oral corticosteroids therapy, 314 ng/mL. The serum TNF-alphaa concentration differed between patients with rhinitis (n = 15) (1.065 pg/mL) and patients with asthma (n = 12) (3.46 pg/mL). Among patients with asthma, TNF-alpha concentrations were similar in all groups classified according to the disease severity. CONCLUSIONS sICAM and ICAM-1 expression correlates with airways diseases severity.

Mild cognitive impairment and depressive symptoms in elderly patients with diabetes: prevalence, risk factors, and comorbidity.

The aim of the study was to estimate the prevalence of mild cognitive impairment (MCI), depressive syndrome cases, and its comorbidity, and to identify predictors of these conditions. Methods. 276 diabetics elders were screened for MCI and depressive symptoms. Detailed information of history of diabetes, and data of BMI, HbA1c, and blood lipids were collected. Results. The prevalence of MCI was 31.5%, depressive syndrome was 29.7%, and MCI with coexisting depressive mood was 9.1%. The logistic regression analysis revealed that variables which increased the likelihood of having been diagnosed with MCI were: higher HbA1c level, previous CVD, hypertension, retinopathy, increased number of comorbidities, and less years of formal education. Significant predictors of having a depressive mood included female gender, single marital status, current and past smoking status, lack of physical activity, higher BMI and total cholesterol level, increased number of comorbidities, history of hypoglycemia, and insulin treatment. Factors associated with both MCI and depressive syndrome were female gender, single marital status, past smoking status, retinopathy, previous CVD or stroke, increased number of comorbidities, and insulin treatment. Conclusions. Depressive symptoms, MCI, and its comorbidity are common in elderly subjects with type 2 diabetes. Systematic screening could result in the identification of high-risk patients.

Correlation between eicosanoids in bronchoalveolar lavage fluid and in exhaled breath condensate

Exhaled breath condensate (EBC) has been increasingly used as a new and non-invasive method to study airway inflammation. In this study we have compared the concentrations of lipid mediators in EBCwith concentrations in bronchoalveolar lavage fluid (BALF). We included 37 patients undergoing bronchoscopy (12 sarcoidosis, 12 COPD, 6 lung cancer, 5 chronic cough, 1 Wegener’s granulomatosis, 1 sclerodermia). Patients were not allowed to have exacerbation or any change in concomitant medication for at least 4 weeks prior to the study. In all patients, EBC was collected immediately prior to the bronchoscopy. The levels of cys-LTs, LTB4, 8-isoprostane were significantly higher in BALF compared to EBC (p < 0.0001, p < 0.001, p < 0.0001 for cys-LTs, LTB4, 8-isoprostane respectively). Moreover, there was a strong positive correlation between both leukotriene B4 and 8-isoprostane in BALF and EBC (r = 0.53 and r = 0.79, p < 0.01, respectively) in patients with sarcoidosis and COPD but there was no correlation between eicosanoids BALF and EBC in patients with chronic cough and lung cancer. This is the first study to compare EBC and BALF in different lung diseases which demonstrated significant correlations between the levels of eicosanoids in BALF and EBCin patientswith COPD and sarcoidosis. EBC may be useful inmeasuring inflammation in several inflammatory lung diseases.

Serum Levels of Inflammatory Markers in Depressed Elderly Patients with Diabetes and Mild Cognitive Impairment

Objective The aim of the study was to determine the serum levels of CRP, IL-6 and TNF-α in elderly diabetic patients with depressive syndrome alone or with coexisting mild cognitive impairment (MCI). Methods 276 diabetics elders were screened for depressive symptoms (using Geriatric Depression Scale: GDS-30) and MCI (using the Montreal Cognitive Assessment: MoCA score). Data of HbA1c, blood lipids and inflammatory markers levels were collected. Results In all groups of patients levels of CRP, IL-6 and TNF-α were significantly higher as compared to controls. The highest level of inflammatory markers was detected in group with depressive mood and coexisting MCI, however IL-6 level didn’t significantly differ as compared to MCI group. We founded correlations between all inflammatory markers in group of patients with depressive mood and in group of subjects with depressive symptoms and coexisting MCI. GDS-30 score was correlated with levels of inflammatory markers in group with depressive mood, and with levels of CRP and TNF-α in group with depressive mood and coexisting MCI. In the group with depressive mood and coexisting MCI we founded that MoCA score was negatively correlated with CRP and TNF-α levels; and HbA1c level was positively correlated with all inflammatory markers. The univariate logistic regression models revealed that variables which increased the likelihood of having been diagnosed with MCI in depressed patients were: higher levels of HbA1c, CRP, IL-6 and TNF-α, previous CVD or stroke, increased number of co-morbidities and microvascular complications, older age, less years of formal education. The multivariable model showed that previous CVD, higher HbA1c and IL-6 levels are significant factors. Conclusions We demonstrated that the presence of depressive syndrome is associated with higher levels of inflammatory markers in elderly patients with diabetes. The presence of MCI in these depressed subjects has additive effect on levels of inflammatory mediators.

Use of Montelukast Alone or in Combination with Desloratadine or Levocetirizine in Patients with Persistent Allergic Rhinitis

Background We assessed the course of treatment in patients with persistent allergic rhinitis (AR) treated with montelukast, levocetirizine, or desloratadine alone or combinations of antihistamine and montelukast. Methods A 32-week randomized, double-blind, placebo-controlled, crossover, double-armed study in 40 adult patients with history of persistent AR, clinical allergy to house-dust mites, and a total nasal symptom score of at least 5 (congestion of at least 2) has been performed. Patients with asthma, chronic obstructive pulmonary disease, nonallergic rhinitis with clinical allergy associated with seasonal allergens, and other serious diseases were excluded. There were four 6-week treatment periods separated by 2-week washout periods. Twenty patients received either montelukast or antihistamine, a combination of montelukast and antihistamine, or placebo. The sequence of treatment was randomly assigned. Nasal symptoms were assessed using a 4-point scale at baseline, daily during the 1st week and on days 14, 21, 28, 35, and 42 of treatment. Results Montelukast alone, levocetirizine alone, desloratadine alone, and the montelukast/antihistamine combinations significantly improved nasal symptoms during the first 24 hours. Improvement gradually increased during the 6 weeks of treatment, especially in patients receiving montelukast alone or in combination therapy with the antihistamine in both arms. Improvement at 42 days of treatment was significantly greater than that achieved on the 1st day of therapy in patients treated with the combination of montelukast and levocetirizine. Conclusion Montelukast alone or in combination with antihistamines gave a gradual increase in nasal symptom improvement within 6 weeks of treatment in patients with persistent AR.

Heart Rate-Lowering Efficacy and Respiratory Safety of Ivabradine in Patients with Obstructive Airway Disease

BackgroundThere is substantial evidence that heart rate (HR) is a powerful predictor of mortality in both normal individuals and in patients with cardiovascular disease. The use of b-adrenoceptor antagonists (β-blockers) has confirmed the importance of lowering elevated HR in a patient’s prognosis. However, these agents can have undesirable adverse effects (AEs) and due to the risk of bronchoconstriction are contraindicated in patients with obstructive airway disease. A selective bradycardic agent, without such undesirable effects, could be of therapeutic interest. Ivabradine, a new Ifinhibitor that acts specifically on the sino-atrial node, is a pure HR-lowering agent.ObjectiveThe objective of this study was to assess HR-lowering efficacy and respiratory safety of ivabradine in patients with asthma and chronic obstructive pulmonary disease (COPD).MethodsThis was a randomized, single-center, double-blind, placebo-controlled, crossover trial. Enrolment began in May 2009, and the last patient completed the study in January 2011. The study was conducted in an ambulatory setting. A total of 40 patients completed the study (20 asthmatic patients and 20 COPD patients). Inclusion criteria were: documented diagnosis of asthma or COPD according to international guidelines, age 18–75 years, and mean HR on Holter ECG recording of ≥60 beats/min. Exclusion criteria included disease exacerbation in a previous month or inability to understand instructions on the study procedures. All patients received ivabradine 7.5 mg twice daily for 5 days and placebo twice daily for 5 days in a crossover manner, in one of the two arms of the study, with at least 2 days of washout between treatments. The main outcome measures included the difference in HR between ivabradine and placebo treatment and change in HR in comparison with baseline. Other evaluated outcomes were differences in the peak expiratory flow rate (PEFR), the daily symptom score, rescue medication consumption, and AEs. Results: Ivabradine produced significantly lower mean HR than placebo in both groups of patients: asthma 67.4 ± 8.38 versus 82.85±11.19 beats/min (p<0.001) and COPD 69.75 ± 8.9 versus 81.05 ± 9.75 beats/min (p<0.001). Similar results were observed for the minimal HR as well as for the maximal noted HR. In comparision with baseline, ivabradine significantly reduced HR in both groups of studied patients (all p < 0.05), whereas placebo did not have such an effect. No significant difference, in either the asthma or the COPD group, was found between ivabradine and placebo in morning and evening peak expiratory flow rate, peak expiratory flow diurnal variability, daily symptom scores, and rescue medication usage (all p > 0.05). Both treatments were well tolerated. The incidence of AEs was low and generally similar in both periods of treatment, except for visual symptoms during treatment with ivabradine, which was reported by 5% of the patients.ConclusionOur study demonstrated that selective HR reduction with ivabradine is effective in patients with asthma and COPD, with no alteration in respiratory function or symptoms over the duration of the study. Ivabradine offers an interesting alternative, as an HR-lowering agent, in patients with respiratory disease and contraindications to β-blockers.Clinical Trial RegistrationRegistered at www.clinicaltrials.gov (NCT01365286).

Intravenous immunoglobulin replacement therapy in the treatment of patients with common variable immunodeficiency disease: an open-label prospective study.

BACKGROUND Common variable immunodeficiency (CVID) is characterized by humoral immunodeficiency resulting in increased susceptibility to infections and diminished responses to protein and polysaccharide vaccines. Intravenous immunoglobulins (IVIgs) constitute a replacement therapeutic regimen for CVID and other primary and selected secondary immunodeficiencies but their mode of action is still not fully understood. OBJECTIVE The purpose of this study was to assess the effect of IVIg replacement therapy on the population of regulatory T cells (cells expressing CD4, CD25 and low levels of CD127) [T(regs)]), plasma levels of interleukin (IL)-2 and IL-10, and expression of fragment, crystallizable γ receptor IIb (Fc γ RIIb) [CD32b] on CD19+ B cells in CVID patients. METHODS This was an open-label prospective trial that included 17 CVID patients and seven healthy subjects as case controls. The diagnosis of CVID was primarily established by clinical criteria designed by the European Society for Immunodeficiencies (ESID) and was confirmed by low serum levels of two out of three subclasses of immunoglobulins (IgG, IgA or IgM). All CVID patients were treated with the IVIg preparation Flebogamma® 5%, a highly purified, pasteurized normal human IgG extracted from the serum of healthy individuals, administered at a dose of 300 mg/kg by slow 2-hour intravenous infusion. Blood samples were collected 30 minutes before the infusion and 30 minutes and 2 weeks after the termination of the infusion. We examined: (i) the plasma levels of IL-2 and IL-10; (ii) the percentage of CD4+ T cells and T(regs); and (iii) the expression of Fc γ RIIb on the surface of CD19+ B cells. RESULTS CVID patients had higher plasma levels of IL-2 (p = 0.045) and IL-10 (p = 0.002) as well as a higher expression of Fc γ RIIb on CD19+ B cells (p =  0.0119) before IVIg compared with healthy controls. The infusion of IVIg led to further increases in the plasma levels of these cytokines 30 minutes after the termination of the infusion versus baseline (IL-2: p =  0.0004; IL-10: p = 0.0003). IVIg did not affect the expression of Fc γ RIIb. Finally, IVIg infusion resulted in elevation of the percentages of CD4+ T cells (p = 0.028) and T(regs) (p = 0.006) in the blood 30 minutes after the infusion. CONCLUSION Flebogamma® 5% as replacement therapy not only supplies immunoglobulins but also modulates the immune response, and in this way may provide additional benefits to patients with CVID.

C-Reactive Protein, Advanced Glycation End Products, and Their Receptor in Type 2 Diabetic, Elderly Patients with Mild Cognitive Impairment

Objective The aim of the study was to evaluate serum levels of advanced glycation end products (AGEs), receptor for advanced glycation end products (RAGE), and C-reactive protein (CRP) in elderly patients with type 2 diabetes mellitus with and without mild cognitive impairment (MCI) and to determine the predictors (including AGEs, RAGE, and CRP levels) of having MCI in elderly patients with type 2 diabetes. Methods Two hundred seventy-six diabetics elders were screened for MCI (using the Montreal Cognitive Assessment: MoCA score). Data of biochemical parameters and biomarkers were collected. Results Serum AGEs, RAGE, and CRP levels were significantly increased in MCI patients compared to controls. In group of patients with MCI, serum RAGE level was positively correlated with AGEs level and with CRP level. RAGE, AGEs, and CRP concentrations were positively correlated with HbA1c levels and negatively correlated with MoCA score. The univariate logistic regression models revealed that variables, which increased the likelihood of diagnosis of MCI in elderly patients with type 2 diabetes were higher levels of HbA1c, RAGE, AGEs, CRP, TG, lower level of HDL cholesterol, previous CVD, HA, or use of HA drugs, hyperlipidemia, retinopathy, nephropathy, increased number of co-morbidities, older age, and less years of formal education. HA or use of HA drugs, previous CVD, higher level of RAGE and CRP, older age and less years of formal education are the factors increasing the likelihood of having MCI in elderly patients with type 2 diabetes in multivariable model. Conclusion In summary, serum AGEs, RAGE, and CRP are increased in the circulation of MCI elderly diabetic patients compared to controls. A larger population-based prospective study needs to be performed to further confirm the relationship between AGEs, RAGE, and the cognitive decline or progress to dementia.