Immunization with 30 μg adjuvanted RSV F nanoparticles elicited s

Immunization with 30 μg adjuvanted RSV F nanoparticles elicited significantly higher serum levels of PCA (884 μg/ml) than animals that received 15 mg/kg (human learn more dose) of palivizumab (86 μg/ml). PCA was below the LOD of the assay (<20 μg/ml) in cotton rats immunized with FI-RSV, and naïve control groups, and slightly above LOD in the RSV A intranasal immunization group (Fig. 1B). Sera from all groups, with the exception of

FI-RSV and placebo recipients, had virus neutralizing antibodies (Fig. 1C). Adjuvanted RSV F elicited higher neutralization titers (GMT = 697) than natural infection (GMT = 95) or palivizumab passively immunized cotton rats (GMT = 320) (Fig. 1C). The neutralizing titer differences observed between cotton rats that received adjuvanted RSV F and virus infected cotton rats were statistically significant (p < 0.01) following the same trend observed from analysis of PCA and anti-RSV F ELISA responses. The in vivo efficacy of RSV F nanoparticle vaccine was evaluated by measuring inhibition of viral

replication in the lungs and nasal passages of immunized cotton rats challenged with RSV. Complete inhibition of virus replication was observed in the lungs of cotton rats immunized with live RSV, RSV F nanoparticles administered with and without adjuvant, as well as palivizumab selleck chemicals given passively ( Fig. 2A). FI-RSV reduced lung viral load (pfu/g tissue; GMT = 2357) when compared to naïve challenged cotton rats (pfu/g tissue; GMT = 194,237) but failed to confer full protection. When viral replication was evaluated in the nasal compartment, only the RSV F vaccine with adjuvant and RSV infection groups were completely protected ( Fig. 2B). Cotton rats that received unadjuvanted RSV F and palivizumab had reduced viral load compared to the naïve animal group but with readily

measurable virus titers in nasal tissue following challenge ( Fig. 2B). When Lot 100 FI-RSV vaccine was used in a clinical trial in the late 1960s, vaccinated children developed enhanced respiratory disease (ERD) upon reinfection [33]. Similarly, ERD can be reproduced in the cotton rat model with the same vaccine, known as Lot 100 FI-RSV vaccine [30] and [31]. In the current 4-Aminobutyrate aminotransferase study, Lot 100 FI-RSV induced prominent alveolitis and perivasculitis in the lungs of RSV challenged animals, consistent with ERD. Conversely, significant lung histopathological changes of this magnitude were not observed in cotton rats immunized with the RSV F nanoparticle vaccine administered with or without adjuvant and were similar to the minimal changes seen in placebo and palivizumab animals (Fig. 3A–C). The RSV F vaccine was derived from the RSV A long sequence. A dose ranging immunization with the RSV F vaccine was undertaken to compare the protective efficacy of the vaccine against a non-homologous challenge (RSV B) with palivizumab, known to be protective against both RSV A and B [34]. Cotton rats were immunized with 0.003, 0.03, 0.3 or 3.

The acute toxicity and lethality (LD50) of the methanol and the c

The acute toxicity and lethality (LD50) of the methanol and the chloroform fractions were determined using mice according to slightly modified method of.5 The chemicals used for this study were of analytical grade and procured

from reputable scientific shops at Nsukka. They included the following: hyoscine butylbromide [standard anti-diarrhoeal drug (Sigma–Aldrich, Inc., St. Louis, USA)], methanol and chloroform (both supplied by BDH Chemicals Ltd., Poole, England), castor oil (laxative) ZD1839 in vitro and 3% (v/v) Tween 80 (vehicle for dissolving the extract). Castor oil-induced diarrhoea was evaluated using the methods of6 and 7 with a little modification. Castor oil-induced enteropooling was determined by the method of8. The data obtained from the laboratory results of Selleck Lumacaftor the tests were subjected to One Way Analysis of Variance (ANOVA). Significant differences were observed at p ≤ 0.05. The results were expressed as means of five replicates ± standard deviations (SD). This analysis was done using the computer software known as Statistical Package for Social Sciences (SPSS), version 16. The result of this investigation shows that there was no lethality or any sign of toxicity in the four groups of three mice each that received 10, 100, 1000 mg/kg body weight of each fraction of the chloroform–methanol extract of the seeds of P. americana and 5 ml/kg

body weight of 3% v/v Tween 80 respectively at the end of the first phase of the study. At the end of the second phase of the study, there was neither death nor obvious sign of toxicity in the groups of mice that received 1900 and 2600 mg/kg body weight of each fraction of the chloroform–methanol extract of the seeds of P. americana. However, there were death and obvious signs of toxicity (such as sluggishness, swollen face and eyes) in the groups of mice administered 5000 mg/kg body weight of the methanol and the chloroform fractions respectively within 24 h of administration. In the castor oil-induced diarrhoea experiment (wetness of faeces

test), the rats in the group that received neither castor oil nor any of the fractions of the chloroform–methanol extract of the seeds of Histone demethylase P. americana (group 1) had significantly (p < 0.05) decreased numbers of wet faeces (0.00 ± 0.00, 0.25 ± 0.50, 0.25 ± 0.50 and 0.00 ± 0.00) at the first, second, third and fourth hours of post-treatment respectively when compared to the values (1.50 ± 1.29, 2.00 ± 0.00, 2.00 ± 1.41 and 1.50 ± 0.58) obtained for rats in the castor oil-treated control group (group 2). The chloroform fraction of the extract at the dose of 200 mg/kg body weight, in a similar manner as the standard anti-diarrhoeal agent (hyoscine butylbromide), inhibited significantly (p < 0.05) the wetness of faeces of rats in group 7 as evidenced by the significant (p < 0.05) reduction in the number of wet faeces of rats in group 7 at the third and fourth hours of post-treatment (0.50 ± 0.82 and 0.50 ± 0.58 respectively) when compared to the values (2.

Therefore, those essential proteins were excluded having sequence

Therefore, those essential proteins were excluded having sequence similarity with human proteome or gut flora. Only 13 proteins can be considered as putative drug targets (Table 1). Toxin secretion ABC transporter, ATP-binding/permease protein. • Biological process: Involved in the biological process pf proteolysis Probable DNA-directed RNA polymerase subunit delta. • Biological process: transcription Regulatory ON-1910 protein spx. • Biological process: Transcription regulation Conserved protein domain with no predicted function. Putative uncharacterized protein with no predicted function. Preprotein translocase SecY family protein • Cellular component: Membrane Putative preprotein translocase, SecG

subunit. Probable DNA-directed RNA polymerase subunit delta. • Biological process: protein secretion Putative uncharacterized protein. Initiation-control protein yabA. • Biological process: DNA replication. Putative ABC transporter, permease protein. Ribociclib solubility dmso In total there were 26 virulent genes which were retrieved from literature and 4508 from the SMD data. No paralogs were found to any gene as gene duplication is a rare phenomenon.19, 20 and 21 All the probable virulent genes were subjected to essentiality test to which only 50 were found to be essential and were subjected to BLAST against gut flora which gave us 32 genes and with humans gave us only 9.

These 9 could be called as putative drug targets. The present study revealed new putative drug targets (genes or their products) against Streptococcus pnemoniae. This putative drug targets may help in the development of novel antibiotics or potential drug targets which could be targeted against S. pnemoniae and these targets should not be similar to the host genome (H. sapiens, E. coli) which may lead to

allergic reactions or toxic effects. The author has none to declare. The Author is Phosphoprotein phosphatase highly thankful to Honorable Vice-Chancellor, Tezpur University Prof Mihir K Choudhuri for start-up research grant to initiate the work and central library Tezpur University for e-resources and databases. “
“Lower respiratory tract infections (LTRIs) are one of the leading causes of death world-wide.1 Urinary tract infections (UTIs) are the second most commonly found in women and it has been estimated that about one-third of adult women have experienced UTIs at least twice.2 A variety of bacterial pathogens are responsible for LRTIs and UTIs, but the most prominent are Escherichia coli, Enterococcus spp., Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter spp., and coagulase-negative staphylococci. 3 and 4 Resistance to antibiotics has increasingly been reported in recent years and most of the pathogens have become resistant to third-generation cephalosporins. 5 Antibiotic resistance being the first cause of failure of therapy particularly in Acinetobacter baumannii, P. aeruginosa, K.

2 and subjected to real-time PCR to determine the amounts of 244

2 and subjected to real-time PCR to determine the amounts of 244 DI RNA, genomic segment 1 RNA, and segment 7 RNA (Fig. 3). The levels of segments 1 and 7 RNA on day 2 after infection were similar in the lungs of mice given either inactivated DI virus + A/WSN or active DI virus + A/WSN. On day 4 there was 5-fold less segment 7 and 12-fold less segment 1 in the active DI virus + A/WSN than MG 132 in the control group but by day 6 both groups had similar amounts of segments 1 and 7. At this point the levels of segments 1 and 7 in the lungs of the inactivated DI virus + A/WSN group reached a plateau, while those in the active DI virus + A/WSN group reached a plateau

from day 8. On day 8 mice in the inactivated DI + A/WSN group were very sick indeed, and the amount of RNA in replicate lungs varied by over 100-fold making the mean unreliable. The majority of mice in this group died shortly thereafter. In both groups, levels of segment 7 RNA were consistently

5 to 10-fold greater than those of segment 1. The reasons for this are unclear but as the PCR primers are vRNA specific this appears to be a genuine difference. This is consistent with studies with studies of synchronized infection of cells in vitro in which segment 7 RNA was 9-fold greater than the combined RNAs1 to 3 [36] or 2-fold greater than RNA 1 early in infection [37]. There was an initial high level of approximately 108 copies of 244 DI RNA in the lungs of SCID mice inoculated with the active DI virus + A/WSN, through and about 100-fold lower in the group Vismodegib in vitro that received inactivated DI virus + A/WSN. The latter represents UV-fragmented 244 RNA and residual intact 244 RNA (Fig. 3c and d). After 2 days there was undetectable 244 DI RNA in the lungs of mice inoculated with inactivated DI virus + A/WSN (Fig. 3c and d), whereas the amount in the active

DI virus + A/WSN group was unchanged. 244 RNA in the active DI virus-protected group then maintained a modest but steady rise to nearly 109 copies per lung by day 8, and remained between 108 and 109 copies until day 16 when most of the mice were dead. The RNA was clearly being replicated as mice that received only active DI virus showed a steady decline in amounts of 244 RNA (Fig. 3d open squares). Thus substantial amounts of 244 RNA were present in mice inoculated with DI + A/WSN throughout both the initial period of good health (up to and including day 9) and through the period of delayed onset disease (days 10–16). In contrast 244 DI RNA in the lungs of mice inoculated with inactivated DI virus + A/WSN increased from day 2 to day 4 reflecting rapid replication of residual amounts of DI RNA that remained after the UV-irradiation (Fig. 3c). The 244 RNA increased to a maximum on day 6, but this was evidently too late to be of benefit as 75% of mice already showed signs of clinical disease on day 4.

6 The compound (3) (0 21 g, 1 mmol, 1 00 equiv) was taken in a ro

6 The compound (3) (0.21 g, 1 mmol, 1.00 equiv) was taken in a round-bottomed flask containing mixture (1:1) of demineralized water, and 4-bromophenol (4d) (0.15 g, GSK-3 inhibitor 1 mmol) was added. The reaction vessel was subjected to heat for 1 h at temperature 60–65 °C, after that the reaction mixture was washed with saturated sodium bicarbonate solution and extracted with ethyl acetate. The solvent was evaporated under reduced pressure to obtain the product 1-(4-acetylphenyl)-3-(4-bromophenoxy) pyrrolidine-2,5-dione, which was washed with hexane and dried under vacuum. 1-(4-acetylphenyl)-3-(1-Napthyloxy)-pyrrolidine-2,5-dione

5a. Brown solid. Yield 85%; M.p. 145° (hexane/MeOH). FTIR (KBr): 1724, 1599, 1520, 1344, 1H NMR (500 MHz, DMSO), 3.45 (DMSO solvent); 2.55 (s, 3H); 3.11 (s, J = 5, 1H); 5.3 (s, J = 10, 1H), 6.64–8.17 (m, 7H), 7.32 (dd, J = 15, 1H), 7.34 (dd, J = 15, 2H). 13C NMR (500 MHz, DMSO) 22, 32, 80.8, 103, 120, 120.1, 121.9, 125, GSK1210151A supplier 126, 127, 129, 133, 134, 145, 170.9, 191 δ ppm; ESIMS m/z 359 (M + ) Anal. Calc. for C22H17NO4 (359.37): C, 73.53; H, 4.77; N, 3.90 Found: C, 73.51; H, 4.75; N, 3.88. 1-(4-acetylphenyl)-3-(2-Napthyloxy)-pyrrolidine-2,5-dione

5b. Brown solid. Yield 86%; M.p. 147° (hexane/MeOH). FTIR (KBr): 1724, 1599, 1520, 1344, 1H NMR (500 MHz, DMSO), 3.45 (DMSO solvent); 2.55 (s, 3H); 3.11 (s, J = 5, 1H); 5.3 (s, J = 10, 1H), 6.52–8.20 (m, Carnitine palmitoyltransferase II 7H), 7.32 (dd, J = 15, 1H), 7.34 (dd, J = 15, 2H). 13C NMR (500 MHz, DMSO) 22.8, 31.1, 80.8, 103.6, 120, 120.3, 121.9, 125, 126, 127, 128.8,

133, 134, 145, 171, 187 δ ppm; ESIMS m/z 360 (M + H) Anal. Calc. for C22H17NO4 (359.37): C, 73.53; H, 4.77; N, 3.90 Found: C, 73.52; H, 4.78; N, 3.91. 1-(4-acetylphenyl)-3-(4-Chlorophenyloxy)-pyrrolidine-2,5-dione 5c. Yellow solid. Yield 88%; M.p. 164° (hexane/MeOH). FTIR (KBr): 1724, 1599, 1520, 1344, 1H NMR (500 MHz, DMSO), 3.45 (DMSO solvent); 2.04 (s, 3H); 2.5 (s, J = 5, 1H); 5.3 (s, J = 10, 1H), 6.52 (dd, J = 10, 1H), 6.55 (dd, J = 10, 1H), 7.32 (dd, J = 10, 1H), 7.34 (dd, J = 10, 2H). 13C NMR (500 MHz, DMSO) 22, 71, 82, 114.8, 118, 120, 128, 132.4, 133, 144, 160, 161, 189 δ ppm; ESIMS m/z 300 (M) – 1; 221, (M) – 2; 144 (M) – 3; 128 (M − 4) Anal. Calc. for C18H14ClNO4 (343.76): C, 62.89; H, 4.10; N, 4.07 Found: C, 62.86; H, 4.1; N, 4.01. 1-(4-acetylphenyl)-3-(4-Bromophenyloxy)-pyrrolidine-2,5-dione 5d. Brown solid. Yield 91%; M.p. 166° (hexane/MeOH). FTIR (KBr): 1724, 1599, 1344, 1H NMR (500 MHz, DMSO), 3.45 (DMSO solvent); 2.04 (s, 3H); 2.5 (s, J = 5, 1H); 5.3 (s, J = 10, 1H), 6.52 (dd, J = 10, 1H), 6.55 (dd, J = 10, 1H), 7.32 (dd, J = 10, 1H), 7.34 (dd, J = 10, 2H).

ESAT-6 is included in Interferon gamma release assay (IGRA) diagn

ESAT-6 is included in Interferon gamma release assay (IGRA) diagnostic test kits. In the present trial, similar to previous H1:IC31® trials, vaccination was associated with a transient conversion of the QFT in about half of the vaccinated subjects. Induction of ESAT-6 specific immune responses by vaccination with an ESAT-6-containing

vaccine may very well interfere with current ESAT-6 based diagnostics. However, this may not pose a major diagnostic problem, as IGRAs are indicated in low endemic settings and TB vaccines will mainly be used in high endemic settings [35]. In conclusion, selleck screening library we report the first in man studies of the CAF01 adjuvant and demonstrate its safety in a phase I trial. Vaccination with CAF01 together with the H1 fusion protein resulted Pazopanib manufacturer in long lasting T-cell immunity characterized by mainly IL-2 and TNF-α producing T-cells indicating that CAF01 is of relevance for future human vaccination studies. The authors gratefully acknowledge partial funding from EC-FP6-TBVAC contract no LSHP-CT-2003-503367 and EC-FP7-NEWTBVAC contract HEALTH.F3.2009 241745 (the text represents the authors’ views and does not necessarily represent a position of the Commission who will not be liable for the use made of such information). We also acknowledge Jannik Godt from JG Consult for analysis of data for the clinical study report. We would like to

thank the TBVI PDT, consisting of Micha GBA3 Roumiantzeff, Barry Walker, Roland Dobbelaer, Juhani Eskola and Georges Thiry and the Data Safety Monitoring Board consisting of Prof. Dr. C.G.M. Kallenberg, University Medical Center Groningen, The Netherlands; Dr. H.C. Rümke, Vaccine Center Rotterdam, The Netherlands and

Prof. Dr. D.J.M. Lewis, Center for Infection St George’s University of London, UK. Conflict of interest statement: PA is co-inventor on a patent application claiming H1 as a vaccine and CAF01 as vaccine adjuvant. All rights have been assigned to Statens Serum Institut, a Danish not-for-profit governmental institute. BTC, EMA, IK, MR, SH and LVA are employed by Statens Serum Institut. The other authors involved in this study have no conflict of interest. “
“Before the influenza pandemic in 2009 most European countries; including Sweden; recommended vaccination only of pregnant women with clinical risk-conditions; e.g. chronic heart diseases [1]. During the pandemic; all pregnant women were considered a priority group for vaccination; based on evidence of an increased risk of severe disease and death associated with the pandemic strain [2]. In the post-pandemic phase; Sweden has decided to recommend pregnant women vaccination against influenza A(H1N1)pdm09 with the trivalent vaccine; as long as influenza A(H1N1)pdm09 continues to circulate and exhibit a higher propensity to cause viral pneumonia than seasonal influenza.

In this study, most of the rotavirus positive children were from

In this study, most of the rotavirus positive children were from 6 to 12 months age groups (Fig. 2), suggesting that the post breast feeding age group is more prone to rotavirus infection. In this study, G9 was the most common strain (40%) responsible for severe diarrhea related hospitalizations (Table 2). Previous studies during 2003–2009, showed that, in the eastern part of India, G1 (>50%) and G2 strains (∼23–33%) were dominant, OSI-744 solubility dmso whereas G9 (2–10%) and G12 (8–17%) strains occurred at lower frequencies [19], [20] and [21], and similar trends were reported

in western, northern and southern parts of India [17], [18], [20], [21] and [22]. During the current study period, G9 Carfilzomib and G2 strains predominated, causing 75% and 62% of all RV infections among hospitalized and OPD cases, respectively. G1 genotypes were still observed at 16–25% (Table 2). Previously available two rotavirus

vaccines have shown high effectiveness against several strains not in the vaccine including G9 and G12 in countries like USA [13] and [15], suggesting there is a heterotypic protection. Still in countries like India, where genotypic diversity is very high, strains like G9 and G12 should be included in the vaccine. The high prevalence of G9 observed in this study suggests that it may be valuable to have a vaccine that includes serotype G9 such as strain 116E, that is currently in the pipeline. Nucleotide sequence based homology analysis with respect to previously reported G9 strains revealed close similarity of Kolkata G9 strains to previously reported lineage III strains from the Indian subcontinent (India, Bangladesh and Nepal) (Fig. 4A). The currently licensed vaccine from India (Rotavac) 116E, has G9P[11] Carnitine palmitoyltransferase II genotype and the G9 strains from Kolkata showed low amino acid homology (89.9–92.6%) with 116E vaccine strain (Table 3), but the vaccine strain was derived from a non-symptomatic neonatal infection and was adapted to cell culture several years ago [10], [11] and [12]. Similarly the circulating lineage II G1 and lineage IV G2 strains were also found to

be distant from the current vaccine strains (Rotarix and RotaTeq). VP7 antigenic domain of Kolkata G1and G2 strains also revealed mismatches with that of vaccine strains (Table 4). Knowledge of currently circulating strains is needed prior to vaccination, for comparison and evaluation during post vaccination studies. Fluctuation of genotypes due to accumulation of point mutations (genetic drift) in the antigenic domain of VP7 gene is one potential reason for changes in circulating strains [53] and [54]. The amino acid analysis of the VP7 antigenic domains compared with vaccine strain was not done earlier in this region. The antigenic variation observed between circulating strains and vaccine strains may influence vaccine efficacy in these settings.

At a mean TIV coverage rate of 83% (range, 53–100%), indirect pro

At a mean TIV coverage rate of 83% (range, 53–100%), indirect protection of non-recipients of the influenza vaccine had a protective effectiveness of 61% (95% confidence interval, 8–83%; P = .03). The overall protective effectiveness (direct and indirect protection) Selleck Temozolomide was estimated to be 59% (95% CI, 5–82%; P = .04). Bearing in mind that this randomised controlled study was over a single season, used TIV rather than LAIV and targeted a slightly narrow age range, the estimate of indirect protection is consistent with that estimated in this paper. The long-term

impact of vaccination on the dynamics of influenza transmission depends in part on the degree of cross protection between different strains, Bioactive Compound Library imparted by the vaccine. This analysis has highlighted the potential importance of herd immunity in preventing influenza in high risk groups. A long-term programme of vaccination may, however, alter the breadth of this herd immunity. The influenza virus evolves away from the herd host immune protection by a process of antigenic shift

and drift [42] and [43]. Each individual host immune system comprises a repertoire of immunities to strains that had previously infected that individual. This natural immunity is long term and has some level of cross-protection against strains not previously experienced by that individual. Thus the natural herd immunity of a population is based on the collective experience of influenza over the last 50 years and is cross-protective to varying degrees against other related strains as well. It can be assumed that vaccine induced immunity is less cross-protective and possibly shorter

lived than natural immunity, although studies of the duration of immunity in naturally exposed individuals and from time series data have proved inconclusive [44] and [45]. If an effective seasonal influenza vaccination strategy were in place for 50 years, the herd immunity of the population will comprise the collective experience of annual influenza vaccination over the last 30 or so years (as the immunity from 30 to 50 years will have waned and natural infection would have been rare). This new herd immunity Isotretinoin will be at a high level, but its antigenic scope may be narrower than the natural herd immunity counterpart, possibly leading to an increased susceptibility to strains that have undergone antigenic drift or shift. Strains that have undergone antigenic shifts have the potential to cause pandemics, as was observed in 2009. These emerging strains typically infect and cause morbidity in younger individuals than those responsible for seasonal influenza [46] and [47]. With the emergence of A(H1N1)v following the 2009 pandemic, this shift in the age distribution of infection towards younger individuals is likely to increase the direct benefits of paediatric vaccination.

The lack of association with the frequency of IFN-γ and IL-4 cell

The lack of association with the frequency of IFN-γ and IL-4 cellular responses and the number of ELISpots generated after stimulation with the five PvMSP9 predicted epitopes supports the recall cellular immune response reported in our previous study [14] and the promiscuous properties

of the PvMSP9 derived peptides: pE, pH, pK, pJ and pL. Several studies have suggested that single-epitope-based vaccines are not potent enough to induce full protection [30], [44] and [45]. However, the identification of immunogenic and promiscuous epitopes within a vaccine candidate antigen is extremely important, since it is possible to formulate a vaccine composed of relevant epitopes from different antigens. Additionally, the combination of multiple B cell and T-cell epitopes was shown to increase immunogenicity [46], [47] and [48]. In conclusion the HLA-DR heterogeneity of the responding subjects and the prediction analysis using selleck screening library the ProPred server strongly

suggest that these peptides was presented to T cells promiscuously. Thus the overall results suggest that HLA restriction will not be a problem if these peptides are used in a vaccine candidate. This work was supported by Brazilian National Research Council–CNPq/PAPES, Fiocruz, National Institute of Health, the Yerkes National Primate Research Center Base Grant #RR00165 awarded by the National Center for Research INCB024360 clinical trial Resources of the National Institutes of Health, and NIH Grant #RO1 AI0555994. Josué da Costa Lima Junior was the recipient of a CNPq Fellowship. We are Dipeptidyl peptidase grateful to all individuals that participate in this study for their cooperation and generous donation of blood, which made this study possible. We thank Eileen Farnon and Jennie Larson for the assistance during the sample collection. We thank the Secretary

of Health of Rondonia State and the Laboratorio Central–LACEN of Rondonia for providing fieldwork support and the Program for Technological Development in Tools for Health-PDTIS/FIOCRUZ for use of its facilities. “
“Asthma is a chronic inflammatory disease of the airways in which eosinophils have a prominent role and are present in sputum, bronchoalveolar lavage (BAL) fluid, and mucosal tissue biopsy samples [1]. Eosinophils are multifunctional leukocytes involved in the initiation and propagation of diverse inflammatory responses, as well as the modulation of innate and adaptive immune responses [2]. Important effector molecules of eosinophils are stored in granules and released upon activation. A prominent molecule is major basic protein, which triggers the degranulation of mast cells and basophiles, and increases smooth muscle reactivity. In addition, eosinophils generate large amounts of the cysteinyl leukotrienes [3], which contribute to the development of airway hyper reactivity (AHR). Eosinophils are produced in the bone marrow from pluripotent stem cells and normally circulate in the blood in low numbers (1–2% of blood leukocytes).

Ils ne modifient pas ou peu le déclin de la fonction respiratoire

Ils ne modifient pas ou peu le déclin de la fonction respiratoire. Une réduction de la mortalité toute cause, observée avec le tiotropium, mériterait d’être confirmée chez les patients les plus à

risque [21] and [22]. Le choix entre un β2-adrénergique et un anticholinergique est fonction du bénéfice symptomatique individuel. L’évaluation de ce bénéfice ne peut se limiter à la mesure de l’augmentation du VEMS, notamment lors d’un test de réversibilité de l’obstruction bronchique, car ce paramètre spirométrique est peu corrélé à l’amélioration clinique find more [23]. D’autres paramètres explorant les voies aériennes distales et la distension pulmonaire pourraient être utiles mais ils ne sont pas encore validés dans ce contexte et ne font pas partie de la pratique courante. Trois agonistes β2-adrénergiques (formotérol, salmétérol, indacatérol) et deux anticholinergiques (tiotropium, glycopyrronium) ont une AMM en France et sont commercialisés. L’aclidinium, autre anticholinergique, a également une AMM. Cependant, faute d’une étude comparative directe d’une durée suffisante avec le tiotropium et bien que les résultats

d’une méta-analyse en réseau confirme l’efficacité bronchodilatatrice similaire des deux produits, l’aclidinium n’a pas obtenu à ce jour de remboursement et n’est pas commercialisé en France. Une AMM européenne PFT�� datasheet vient d’être accordée à l’olodatérol, un nouvel agoniste β2-adrénergique, et à l’uméclidinium, un nouvel anticholinergique (tableau I). L’efficacité sur les symptômes, la qualité de vie et la prévention des exacerbations est globalement du même ordre pour ces médicaments. until La réduction des exacerbations est un critère important d’efficacité qui permet de considérer

que ces médicaments modifient le cours de la maladie. Bien qu’une étude récente de grande ampleur ait pu montrer des différences sur la survenue d’exacerbations en faveur du tiotropium par rapport au salmétérol [24], la pertinence clinique de ces différences est incertaine. Il en est de même des différences en faveur de l’indacatérol sur la qualité de vie par rapport au tiotropium ou sur la réduction de la dyspnée par rapport au tiotropium et au salmétérol. Chez les patients qui reçoivent un traitement par bronchodilatateur de longue durée d’action, un traitement par bronchodilatateur de courte durée d’action peut être prescrit à la demande pour soulager des accès dyspnéiques en privilégiant l’autre classe pharmacologique de bronchodilatateur. En cas de réponse cliniquement insuffisante à un bronchodilatateur de longue durée d’action après vérification du bon usage du système d’inhalation, on peut changer de molécule (si la première instituée n’a apporté aucun bénéfice) ou envisager d’associer deux molécules (si la première instituée a eu une efficacité jugée réelle mais insuffisante). Les bénéfices des associations de bronchodilatateurs de longue durée d’action sont essentiellement observés sur la fonction respiratoire (VEMS).