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Background: IVX-0142 is a heparin-derived hypersulfated disaccharide devoid of anticoagulant activity while possessing anti-allergic and anti-inflammatory activity in preclinical studies. In a proof-of-concept study, the allergen inhalation challenge model was used to investigate the effect of IVX-0142 in mild atopic asthma. Methods: Nineteen subjects, not on controller medications, were randomized to an evaluator-blind, placebo-controlled, cross-over study. The effect of a single nebulized dose of IVX-0142 (80 mg) or placebo administered 30 min prior to allergen inhalation was evaluated on the allergic airway responses, airway responsiveness, and airway inflammation. Results: When compared with placebo, 14 and 13 subjects experienced a relatively smaller maximum fall in forced expiratory volume in 1 s (maxFEV1%) for the early airway response (EAR) and late airway response (LAR) with IVX-0142, respectively ( P < 0.01). The degree of attenuation in the EAR [maxFEV1% (mean ± SE) 26.5 ± 2.8% vs placebo 31.0 ± 2.8%, P = 0.059] and LAR (15.6 ± 2.9% vs placebo 19.0 ± 2.9%, P = 0.24) with IVX-0142, however, was small and did not reach statistical significance compared with placebo. Similarly, a trend in the attenuation of allergen-induced increase in the absolute sputum cell counts was also observed. No difference in the allergen-induced increase in airway hyper-responsiveness and exhaled nitric oxide was noticed. Conclusions: The majority of mild atopic asthmatics demonstrated a reduction in the EAR and LAR to IVX-0142. However, the treatment effect observed with a single prechallenge dose of IVX-0142 was small and heterogeneous. The potential anti-allergic and anti-inflammatory effects using multiple higher doses need to be evaluated. [ABSTRACT FROM AUTHOR]

Background:  Dendritic cells are key contributors to initiation and maintenance of T-cell immunity to inhaled allergen. The purpose of this study was to enumerate the changes in peripheral blood myeloid (mDCs) and plasmacytoid dendritic cells (pDCs), the DCs expressing chemokine receptor 6 (CCR6) and chemokine receptor 7 (CCR7), following diluent and allergen inhalation in asthmatic subjects. Methods:  Peripheral blood was obtained from 16 allergic asthmatic subjects before and at 0.5, 1, 2, 3, 4, 6, 24, and 48 h after inhaled diluent and allergen challenges. Dendritic cells were enumerated using flow cytometry. Results:  Allergen inhalation significantly reduced mDCs at 6 h (21.3 ± 2.0 vs 15.0 ± 1.8/μl blood; P < 0.05) and 24 h (21.5 ± 3.4 vs 16.4 ± 2.4/μl blood; P < 0.05) after challenge. Circulating pDCs were significantly lower than baseline up to 24 h after both allergen and diluent challenges. There was a significant efflux of CCR6+ mDCs from peripheral blood at 6 h and CCR6+ pDCs at 4 h after allergen challenge, when compared with diluent. There was no difference in the number of circulating CCR7+ mDCs or pDCs after diluent or allergen challenges. Conclusions:  Peripheral blood mDCs and CCR6+ mDCs, but not pDCs, are reduced up to 24 h after allergen inhalation. Thus, allergen inhalation causes trafficking of immature CCR6+ DCs from blood into the airway, while that of the trafficking of the mature CCR7+ DCs from the airways into the regional lymph nodes probably occurs through the lymphatic system. [ABSTRACT FROM AUTHOR]

Background The world-wide AIDS epidemic is reflected in Western Europe in an increasing number of HIV-infected persons who originate from Africa. We describe the characteristics and response to antiretroviral therapy (ART) of HIV-infected patients born in Africa and living in France. Methods Analysis of data from the (Anti PROtéase COhorte APROCO) cohort study of HIV-infected patients initiating ART was carried out. Included in the study were 90 patients born in sub-Saharan Africa, 53 in North Africa and 771 in metropolitan France. Results At baseline, there was a higher proportion of women and of the heterosexual transmission route of infection among patients born in sub-Saharan Africa, a higher proportion of injecting drug users among patients born in North Africa and a higher frequency of unemployment and of unstable housing conditions among patients born in both sub-Saharan and North Africa as compared with patients born in France. The median CD4 cell count was lower in patients born in both sub-Saharan and North Africa (sub-Saharan Africa: 197 cells/μL; North Africa: 222 cells/μL) than in patients born in France (307 cells/μL). Median HIV-1 viral loads were similar. After a median follow-up time of 36 months (2506 patient-years), the Kaplan–Meier estimations of probability of survival without new AIDS-defining events were not different. After 36 months of ART, in multivariate analysis, median CD4 cell count, CD4/CD8 ratio and viral load were not statistically different according to birthplace, but the median CD4 percentage was lower in patients born in both sub-Saharan and North Africa. The adherence profiles were similar. Conclusions Although clinical response and adherence to ART did not appear to differ in patients according to their birthplace, the reasons for the more advanced HIV infection observed at ART initiation among patients born in Africa should be further investigated. [ABSTRACT FROM AUTHOR]

Background Inhibition of DNA polymerase γ by nucleoside reverse transcriptase inhibitors (NRTIs) can cause mitochondrial dysfunction and cellular toxicity. Hyperlactataemia, which is a consequence of a shift in the metabolism of pyruvate, is an indicator of nucleoside-related mitochondrial toxicity. Methods We evaluated exercise and oxidative capacities as well as circulatory and ventilatory responses to exercise in 24 HIV-infected patients on NRTIs presenting hyperlactataemia [mean (±standard deviation) fasted lactate=3.5±1.1 mmol/L]; 27 NRTI-treated patients with normal baseline lactate concentrations were used as controls (mean fasted lactate=1.6±0.3 mmol/L). Results In the patients with hyperlactataemia, the average peak work capacity (1.7±0.6 W/kg) and peak oxygen consumption (VO2) (21±4 mL/kg/min) were significantly lower ( P<0.01) than in control subjects (work, 2.1±0.4 W/kg; VO2, 25±4 mL/kg/min). The capacity to increase oxygen extraction during exercise was significantly diminished in the hyperlactataemia group, as shown by a low peak systemic arteriovenous oxygen difference (a-vO2) difference compared with controls (11±3 vs 14±3 mL/dL; P=0.008), and as indicated by a linear correlation between VO2 and systemic a-vO2 difference ( r2=0.76). During exercise, the increases in cardiac output relative to VO2 (mean Δ cardiac output (Q)/ΔVO2=8±3.6) and ventilation (mean Δ ventilation (VE)/ΔVO2=48.6±13.2) were significantly higher in hyperlactataemia patients compared with controls (mean cardiac output Δ(Q)/ΔVO2=6±2; mean ΔVE/ΔVO2=42±12.7; P=0.03). Conclusions The degree of exercise limitation in patients with nucleoside-related mitochondrial toxicity correlates directly with the severity of impaired muscle oxidative phosphorylation, as indicated by the capacity for muscle oxygen extraction. Exaggerated circulatory and ventilatory responses to exercise are direct consequences of the level of impaired muscle oxidative phosphorylation. [ABSTRACT FROM AUTHOR]

Background The predominance of T-helper type 2 (Th2) lymphocytes is thought to underlie the pathogenesis of asthma. Allergen inhalation challenge in atopic asthmatic subjects is associated with decreased interferon-γ (IFN-γ) positive CD4+ and CD8+ lymphocytes in peripheral blood and induced sputum. Objective This study examined the effects of an inhaled corticosteroid on these previously described allergen-induced changes in circulating Th1 and Th2 lymphocytes. Methods Subjects were randomized to 7 days of placebo, 40 or 80 μg ciclesonide in a crossover study. Airway responses and peripheral blood were measured before and after treatment, and 24 h after allergen challenge. Results Ciclesonide 40 and 80 μg significantly attenuated the late response and sputum eosinophils at 8 h post-allergen ( P<0.05). Circulating IFN-γ positive CD4+ lymphocytes decreased after allergen challenge with placebo ( P<0.05), and this was inhibited by 40 μg ciclesonide treatment ( P<0.05). There was no effect of allergen inhalation or ciclesonide on IL-4-positive CD4+ lymphocytes or IFN-γ and IL-4-positive CD8high lymphocytes. The allergen-induced change of IFN-γ/IL-4 ratio on CD4+ cells correlated with the allergen-induced change of peripheral blood eosinophils. Conclusions The results of this study suggest that attenuation of allergen-induced airway responses by ciclesonide may be mediated through regulation of IFN-γ-positive CD4+ cells. [ABSTRACT FROM AUTHOR]

Background: Ciclesonide exhibits clinical efficacy at 160 μg (ex-actuator) once daily but the anti-inflammatory effects at this dose are not known. We wished to know whether 4 weeks therapy with ciclesonide pMDI 160 μg once daily in the morning exhibited significant anti-inflammatory effects. Methods: Seventeen patients with mild persistent asthma (FEV1 3.35 l) were recruited into a double-blind placebo-controlled randomized crossover study. Measurements were made after ciclesonide and placebo treatment as well as after run-in and washout periods, for adenosine monophosphate (AMP) bronchial challenge (primary variable), exhaled nitric oxide (NO) and induced sputum (in a subgroup). Results: The mean (SEM) AMP bronchial challenge PC20 following ciclesonide (140 (63) mg/ml) was significantly ( P < 0.001) increased compared with placebo (17 (8) mg/ml), run-in (13 (5) mg/ml) and washout (9 (3) mg/ml) periods. This amounted to an eightfold (CI: 5.3–12.0) for ciclesonide vs placebo. Likewise, there were significant improvements in exhaled NO levels and a significant reduction in induced sputum eosinophil cell counts. Conclusion: We have shown that inhaled ciclesonide given at 160 μg once daily in the morning exhibits significant anti-inflammatory effects that are in keeping with the previously described clinical effects. [ABSTRACT FROM AUTHOR]

To evaluate the effect of a single nasal allergen challenge on peripheral blood eosinophil/basophil (Eo/B) progenitor cells and induced sputum eosinophil counts in subjects with allergic rhinitis.Sixteen adults entered a sequential nasal control and allergen challenge study, outside the pollen season. Blind assessment of peripheral blood Eo/B progenitor colony forming units (CFU), induced sputum and nasal lavage cell counts was made before and 24 h after both challenges. Subjects recorded their rhinitis symptoms and nasal peak inspiratory flow, hourly at home, following both challenges.When comparing the values 24 h after the control vs. the allergen challenge, there were no significant differences in Eo/B progenitor CFU (control (mean, SD): 3.6 (1.0)/106 cells; allergen: 4.4 (1.1)/106 cells) or sputum eosinophils (control (median, inter-quartile range): 1.0 (0.3–1.7)%; allergen: 0.7 (0.0–1.3)%) despite a significant increase in the percentage (median (inter-quartile range) of eosinophils in nasal lavage (control: 0.6 (0.1–0.9)%; allergen; 1.9 (0.9–8.1)% and significant worsening of nasal peak inspiratory flow and rhinitis symptoms.Despite a significant increase in nasal symptoms and lavage eosinophil counts, a single nasal allergen challenge was not sufficient to elicit a measurable haemopoietic response in circulation, or an increase in sputum eosinophil counts. [ABSTRACT FROM AUTHOR]

In the context of HIV infection and antiretroviral therapy, adiponectin concentrations have been shown to be related to lipodystrophy, metabolic alterations and HIV-protease inhibitor (PI) use. The replacement of PI by nevirapine has improved the lipid profile of patients under antiretroviral therapy. The aim of the present study was to examine whether adiponectin concentration or insulin sensitivity level correlate with the modifications of lipid parameters after the switch of PI by nevirapine. The evolution of metabolic parameters before and after 6 months of substitution of nevirapine for protease inhibitors was evaluated in a cohort of 55 HIV-1 infected patients. Adiponectin concentration, insulin sensitivity, lipid profile, cholesterol ester transfer protein (CETP) mass concentration and triglyceride enrichment of HDL were determined before and after the replacement of PI by nevirapine. Insulin sensitivity was evaluated by the HOMA model assessment. Twenty-four weeks of treatment with nevirapine improved significantly the lipid profile with a significant reduction of apoB (from 0·98 to 0·92 g L−1; P = 0·005) and triglyceride (from 2·02 to 1·66 mmol L−1; P = 0·02). HDL cholesterol and apoA1 increased significantly (from 0·99 to 1·19 mmol L−1; P = 0·001 and from 1·40 to 1·57 g L−1; P < 0·001, respectively). The triglyceride enrichment of HDL significantly decreased after the replacement of PI by nevirapine (from 0·248 ± 0·092 to 0·213 ± 0·093; P = 0·003). At baseline, and after 24 weeks of nevirapine treatment, we observed significant correlations between adiponectin level and lipid parameters [(HDL-cholesterol ( r = 0·66, P = 0·001 and r = 0·69, P = 0·001); triglycerides ( r = −0·42, P = 0·002 and r  =−0·57, P = 0·001), and triglyceride enrichment of HDL ( r = −0·43, P = 0·005 and r = −0·53, P = 0·005)]. Twenty-four weeks of treatment with nevirapine did not significantly change adiponectin concentrations (from 984 to 1086 µg L−1, P = 0·22), CETP mass and insulin sensitivity. This study shows that even though a strong correlation was found between adiponectin and some metabolic parameters at baseline and after 24 weeks of treatment by nevirapine, the improvement of lipid profile observed after the replacement of PI by nevirapine was not in relation to the change of plasma adiponectin concentration. The significant decrease of triglyceride enrichment of HDL after the replacement of PI by nevirapine probably leads to a decreased catabolism of HDL lipoprotein, and consequently explains the increase of plasma HDL concentration observed in this study. Eur J Clin Invest 2004; 34 (8): 569–575 [ABSTRACT FROM AUTHOR]

Background Abnormalities in lipid levels and lipodystrophy (LD) have been commonly reported after commencement of highly active antiretroviral therapy (HAART). A major mechanism by which plasma low-density lipoprotein (LDL) cholesterol levels may be influenced is via the regulation of hepatic LDL receptor expression. The activity of LDL receptors is under hormonal control. Moreover, HIV infection and HAART are associated with important modifications of hormonal status. As the cause of these adverse reactions is unknown, the effects of HAART and lipodystrophy on LDL receptors were evaluated. Materials and methods Thirty-nine HIV treated patients (21 with a protease inhibitor (PI) containing regimen, 18 without PI use) and 22 control subjects were tested for insulin resistance (HOMA model assessment), lipid profile, serum concentration of dehydroepiandrosterone (DHEA) and LDL-R expression. LDL-R on mononuclear cells were quantified by flow cytrometry. Results Among the 39 HIV infected patients, 14 patients had a lipodystrophy (LD). Patients with LD had significantly higher levels of triglyceride (TG) and insulin resistance compared to patients without LD. There was no significant difference in LDL-R count between patients with or without PI use. In contrast, LDL-R count was significantly lower in patients with LD compared with those without (8504 ± 3901 vs. 13 200 ± 4532, P= 0.001). There was no difference in LDL-R count between patients without LD and control subjects. Patients with LD had lower levels of DHEA compared to patients without LD. In HIV-infected patients, we found a significant correlation between LDL-R expression and TG (r = -0·32; P= 0·04) and LDL cholesterol (r=-0·33; P= 0·04). In contrast, we did not observe a correlation between DHEA level and LDL-R count or LDL cholesterol level. Conclusions HIV-lipodystrophy is associated with a lower expression of LDL-R. This decreased expression of LDL-R seems... [ABSTRACT FROM AUTHOR]

Aims: The aim of the present study was to describe the real-life usage patterns of paracetamol., Methods: The Echantillon Généraliste de Bénéficiaires (EGB) database, the permanent 1/97 representative sample from the French national healthcare insurance system, was searched in 2011 to identify usage patterns, concomitant chronic diseases and use of cardiovascular medication in users prescribed single-ingredient (SP) and combination (CP) paracetamol, representing 85% of all sales., Results: Of 526 108 subjects aged ≥15 years in the EGB, 268 725 (51%) had paracetamol dispensed on ≥1 occasion; of these, 207 707 (77%) were dispensed only SP and 61 018 (23%) received CP with or without SP. SP users were younger (48.3 years vs. 50.5 years), and 57% of SP users vs. 58% of CP users were female. Chronic comorbidities were more common in CP than SP users. SP users had, on average, 3.4 dispensings per year vs. 5.0 for CP users, for 36 defined daily doses (DDD, 3 g) of SP vs. 53 DDD per year for CP; 49% SP users bought 14 DDD or fewer; 15% bought >60 DDD. Use of paracetamol increased with age from about 16 DDD per year in 15-30-year-olds to over 90 DDD per year in patients above the age of 75; 53% of patients ≤60 years bought fewer than 14 DDD per year, whereas 55% of those >60 bought more than 30 DDD per year. More than half the dispensings exceeded the legal per-box limit of 8 g., Conclusions: Over 50% of the French adult population were dispensed paracetamol at least once over the course of a year, generally for short-term use. Considering recent misgivings on the real efficacy and safety of paracetamol, such widespread use might have important public health consequences., (© 2016 The British Pharmacological Society.)

Aims: Most risks of nonsteroidal anti-inflammatory drugs (NSAIDs) are pharmacological, dose and duration dependent. Usage patterns of prescription-only (POM) or 'over-the-counter (OTC)' NSAIDs may influence risks, but are not commonly described., Methods: The Echantillon Généraliste de Bénéficiaires database, the permanent 1/97 representative sample from the French national healthcare insurance systems, was queried over 2009-2010 to identify usage patterns, concomitant chronic diseases and cardiovascular medication in OTC and POM NSAID users., Results: Over 2 years, 229 477 of 526 108 patients had at least one NSAID dispensation; 44 484 patients (19%) were dispensed only OTC NSAIDs (93% ibuprofen) and 121 208 (53%) only POM NSAIDs. The OTC users were younger (39.9 vs. 47.4 years old) and more often female (57 vs. 53%); 69% of OTC users and 49% of POM users had only one dispensation. A mean of 14.6 defined daily doses (DDD) were dispensed over 2 years for OTC vs. 53 for POM; 93% OTC vs. 60% POM patients bought ≤ 30 DDD over 2 years, and 1.5 vs. 12% bought ≥ 90 DDD. Chronic comorbidities were found in 19% of OTC users vs. 28% of POM users; 24 vs. 37% had at least one dispensation of a cardiovascular drug over the 2 years., Conclusions: Most of the use of NSAIDs appears to be short term, especially for OTC-type NSAIDs, such as ibuprofen. The validity of risk estimates for NSAIDs extrapolated from clinical trials or from observational studies not including OTC-type usage may need to be revised., (© 2013 The British Pharmacological Society.)