Long-lasting leukocytosis in patients with schizophrenia treated with clozapine after electroconvulsive therapy : ECT stabilizes white blood cell count.

INTRODUCTION: The present study was conducted to investigate the possible hematologic impact of long-term electroconvulsive therapy (ECT) in patients with drug-resistant schizophrenia and receiving clozapine therapy. SUBJECTS AND METHODS: In this retrospective study, clinical charts of 57 hospitalized patients with schizophrenia who required clozapine therapy because of active psychotic symptoms resistant to other antipsychotics were examined. For 18 who underwent ECT, the first assessment was conducted at the end of that therapy (average two months after start, 7.68 sessions) and the second two months later. As for the 39 patients who did not undergo ECT, the first and second assessment points were at two and four months, respectively, after a randomly chosen time point. RESULTS: Multiple regression analysis revealed that modified ECT (m-ECT) (ß = 0.346, p = 0.005), gender (males showed greater increase) (ß = 0.273, p = 0.023), and disease duration (longer associated with greater increase) (ß = 0.258, p = 0.033) were correlated with a change in white blood cell (WBC) count (ΔR2 = 0.277, p < 0.001) at the first assessment point. At the second assessment point, multiple regression analysis showed that m-ECT (ß = 0.262, p = 0.039), gender (males showed greater increase) (ß = 0.264, p = 0.036), and disease duration (longer associated with greater increase) (ß = 0.234, p = 0.068) were again correlated with changed WBC count (ΔR2 = 0.203, p < 0.007). DISCUSSION: An increase in leukocytes may have a protective influence against the adverse myelosuppressive effects of clozapine. However, a simple mobilization of leukocytes from bone marrow to peripheral circulation may not enhance the immune system, leading to only a masking of the effects of a potential immuno-insufficient state in the treated patient. In either case, should leukocytosis be induced and then remain for an extended period, hematologists, as well as psychiatrists involved in electroconvulsive intervention for clozapine-treated patients, must keep this factor in mind.

Knockdown of miR-26a in zebrafish leads to impairment of the anti-inflammatory function of TnP in the control of neutrophilia.

Our recent data show the valuable potential of TnP for the development of a new and safe anti-inflammatory drug due to its ability to control the traffic and activation of leukocytes in response to inflammation. Although there is considerable knowledge surrounding the cellular mechanisms of TnP, less is known about the mechanistic molecular role of TnP underlying its immunomodulatory functions. Here, we conducted investigations to identify whether miRNAs could be one of the molecular bases of the therapeutic effect of TnP. Using a zebrafish model of neutrophilic inflammation with a combination of genetic gain- and loss-of-function approaches, we showed that TnP treatment was followed by up-regulation of only four known miRNAs, and mature dre-miR-26a-1, herein referred just as miR-26a was the first most highly expressed. The knockdown of miR-26a ubiquitously resulted in a significant reduction of miR-26a in embryos, accompanied by impaired TnP immunomodulatory function observed by the loss of the control of the removal of neutrophils in response to inflammation, while the overexpression increased the inhibition of neutrophilic inflammation promoted by TnP. The striking importance of miR-26a was confirmed when rescue strategies were used (morpholino and mimic combination). Our results identified miR-26a as an essential molecular regulator of the therapeutic action of TnP, and suggest that miR-26a or its targets could be used as promising therapeutic candidates for enhancing the resolution of inflammation.

Phenotypic analysis of pyrin-associated autoinflammation with neutrophilic dermatosis patients during treatment.

OBJECTIVE: In 2016 specific heterozygous gain-of-function mutations in the Mediterranean fever gene MEFV were reported as causal for a distinct autoinflammatory disease coined pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). We sought to provide an extended report on clinical manifestations in PAAND patients to date and evaluate the efficacy and safety of treatment with the IL-1-blocking agent anakinra. METHODS: We undertook an open-label pilot study with anakinra. Three patients were recruited in a preliminary phase of the study with the intention to expand the treatment cohort in case of a favourable response. Acute-phase reactants and plasma cytokine levels were monitored throughout. Skin biopsies at baseline and at week 12 were stained for relevant cytokines. Available clinical data on treatment responses were retrospectively collected on additional patients. RESULTS: The three patients from the preliminary phase of the study [patients 1-3 (P1-P3)] demonstrated one failed and two partial treatment responses, where one patient opted to continue treatment with anakinra and the other favoured adalimumab. While a partial systemic response was observed, there was no appreciable effect of anakinra on the prominent cutaneous manifestations, reflected in residual local inflammatory cytokine expression in lesional skin. These observations did not warrant further expansion of the treatment cohort. Clinical data was retrospectively collected on an additional eight patients (P4-P11), highlighting both dominant and recessive inheritance with variable penetrance in PAAND and common gastrointestinal involvement that was not previously appreciated. CONCLUSION: In our experience, while anakinra appears safe, it was not superior to biologicals targeting TNF-α in PAAND despite evidence directly implicating dysregulated IL-1ß signalling.

Systemic Administration of Calea pinnatifida Inhibits Inflammation Induced by Carrageenan in a Murine Model of Pulmonary Neutrophilia.

OBJECTIVE: The aim of this study was to investigate the anti-inflammatory effects of the crude extract (CE), derived fraction, and isolated compounds from Calea pinnatifida leaves in a mouse model of pulmonary neutrophilia. METHODS: The CE and derived fractions, hexane, ethyl acetate, and methanol, were obtained from C. pinnatifida leaves. The compounds 3,5- and 4,5-di-O-E-caffeoylquinic acids were isolated from the EtOAc fraction using chromatography and were identified using infrared spectroscopic data and nuclear magnetic resonance (1H and 13C NMR). Leukocytes count, protein concentration of the exudate, myeloperoxidase (MPO) and adenosine deaminase (ADA), and nitrate/nitrite (NO x ), tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1ß), and interleukin-17A (IL-17A) levels were determined in the pleural fluid leakage after 4 h of pleurisy induction. We also analyzed the effects of isolated compounds on the phosphorylation of both p65 and p38 in the lung tissue. RESULTS: The CE, its fractions, and isolated compounds inhibited leukocyte activation, protein concentration of the exudate, and MPO, ADA, NO x , TNF-α, IL-1ß, and IL-17A levels. 3,5- and 4,5-di-O-E-caffeoylquinic acids also inhibited phosphorylation of both p65 and p38 (P < 0.05). CONCLUSION: This study demonstrated that C. pinnatifida presents important anti-inflammatory properties by inhibiting activated leukocytes and protein concentration of the exudate. These effects were related to the inhibition of proinflammatory mediators. The dicaffeoylquinic acids may be partially responsible for these anti-inflammatory properties through the inhibition of nuclear transcription factor kappa B and mitogen-activated protein kinase pathways.

Heart disease associated to eosinophilia

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C/EBPε ΔRS derived from a neutrophil-specific granule deficiency patient interacts with HDAC1 and its dysfunction is restored by trichostatin A.

CCAAT/enhancer binding protein epsilon (C/EBPε), a myeloid-specific transcription factor, plays an important role in granulopoiesis. A loss-of-function mutation in this protein can result in an abnormal development of neutrophils and eosinophils, known as neutrophil-specific granule deficiency (SGD). The transcriptional activity of C/EBPε is regulated by interactions with other transcription factors and/or post-translational modification, including acetylation. Previously, we reported a novel SGD patient who had a homozygous mutation for two amino acids, arginine (R247) and serine (S248), which were deleted in the basic leucine zipper domain of C/EBPε (ΔRS) and exhibited loss of transcriptional activity with aberrant protein-protein interactions. In the present study, we found that a single amino acid deletion of either R247 (ΔR) or S248 (ΔS) was sufficient for the loss of C/EBPε transcriptional activity, while an amino acid substitution at S248 to alanine in C/EBPε (SA) had comparable transcriptional activity with the wild-type C/EBPε (WT). Although acetylation at lysine residues (K121 and K198) is indispensable for C/EBPε transcriptional activity, an acetylation mimic form of ΔRS (ΔRS-K121/198Q) did not exhibit the transcriptional activity. Interestingly, we discovered that ΔRS, ΔR, ΔS, and ΔRS-K121/198Q interacted with histone deacetylase 1 (HDAC1), whereas WT and SA did not. Furthermore, the proteoglycan 2/eosinophil major basic protein induction activity of ΔRS, ΔR, and ΔS could be restored by the HDAC inhibitor, trichostatin A (TSA), and protein-protein interactions between ΔRS and Gata1 could also be recovered by TSA treatment. Taken together, our results show that TSA has the potential to restore the transcriptional activity of ΔRS, indicating that the inhibition of HDAC1 could be a molecularly targeted treatment for SGD with ΔRS.

Effect of Qinghuang Powder () Combined with Bupi Yishen Decoction () in Treating Patients with Refractory Cytopenia with Multilineage Dysplasia through Regulating DNA Methylation.

OBJECTIVE: To explore the effect of Qinghuang Powder (QHP,()combined with Bupi Yishen Decoction (BPYS, ) on myelodysplastic syndromes (MDS) patients with refractory cytopenia with multilineage dysplasia (RCMD) and determine the change of DNA methylation in MDS-RCMD patients after the treatment of Chinese medicine formula. METHODS: All 308 MDS-RCMD patients were treated with QHP combined with BPYS for 2 months at least, absolute neutrophil count (ANC), hemoglobin (Hb), platelets (PLT), primitive bone marrow cells and chromosome karyotype were chosen as the main evaluation indexes to analyze the treatment effect according to criteria from the MDS International Working Group. Then 43 bone marrow samples from 15 MDS-RCMD patients and 28 healthy donors were obtained for the examination of DNA methylation. Gene Ontology (GO) and Pathway analysis were applied to analyze the methylation data. RESULTS: The overall MDS response rate to QHP was 61.68% (190/360) including hematologic improvement-neutrophil (HI-N) or hematologic improvement-erythroid (HI-E) or hematologic improvement-platelet (HI-P). Patients with anemia had a better response rate than patients with neutropenia or thrombocypenia (55.88% vs 31.54% or 55.88% vs. 36.9%). The DNA methylation microarray analysis disclosed that 4,257 hypermethylated genes were demethylated upon the treatment with QHP and BPYS. GO analysis and Pathway analysis showed that these demethylated genes were involved in a lot of tumor-related pathways and functions. CONCLUSIONS: QHP combined with BPYS could effectively treat MDS-RCMD patients through hematologic improvement (HI-N, HI-P or HI-E) and PLT and RBC transfusion independence due to the demethylation, thereby providing another choice for the treatment of patients with MDS-RCMD.

Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K)-γ Inhibitors.

In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as 15, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound 15 was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally.

Aumento en los recuentos de leucocitos y neutrófilos durante las primeras 18 semanas de tratamiento con clozapina en pacientes ingresadas en una unidad de cuidados psiquiátricos prolongados / Increase in white cell and neutrophil counts during the first eighteen weeks of treatment with clozapine in patients admitted to a long-term psychiatric care inpatient unit

Material y métodos. Se estudió una muestra de mujeres ingresadas en nuestra UCPP y en tratamiento con clozapina. Se estudió la variación de los recuentos de leucocitos y neutrófilos durante las primeras 18 semanas de tratamiento, la aparición de leucopenia, neutropenia y agranulocitosis, así como la influencia de los fármacos empleados de forma concomitante. Resultados y conclusiones. Se obtuvo una tasa de incidencia de neutropenia de 1,82% (IC 95%: 0,05-10,13) y ningún caso de leucopenia ni agranulocitosis (0%). En el análisis cuantitativo de leucocitos y neutrófilos durante las 18 semanas de tratamiento, se observó un aumento hasta la semana 3-4, tendiendo después a la estabilización de las cifras alcanzadas, pero manteniendo siempre cifras superiores a las de los valores iniciales. Estas diferencias resultaron estadísticamente significativas para los leucocitos en el ANOVA de medidas repetidas con la corrección de Greenhouse-Geisser F (11,47, 37)=2,114 (p=0,011), ŋ2P=0,038. También resultó significativo para los neutrófilos el ANOVA con la corrección de Greenhouse-Geisser F (10,33, 37)=3,312 (p=0,0002), y el MANOVA F (18, 37)=2,693 (p=0,005), ŋ2P=0,567). La influencia de los fármacos estudiados de forma concomitante (litio, valproico y biperideno) no resultó globalmente significativa (MANOVA) sobre el aumento hallado en los leucocitos y neutrófilos

Introduction. Clozapine is an antipsychotic drug that has shown to be more effective than other antipsychotics in the treatment of schizophrenia, but its use is limited due to its side effects, particularly by the risk of causing agranulocytosis. A study was made on the variations in white cell and neutrophil counts in patients treated with clozapine in a Long-term Psychiatric Unit. Methods. A retrospective observational study was conducted with a sample of women of our long-term psychiatric care unit who had been treated with clozapine. A study was made on the variations in white cell and neutrophil counts during the first 18 weeks of treatment, as well as the onset of leukopenia, neutropenia, agranulocytosis, and the influence of concomitant drugs. Results and conclusions. The study included 55 patients on treatment with clozapine. The incidence rate of neutropenia was 1.82% (95% CI; 0.05-10.13). The incidence rate of leukopenia and agranulocytosis was 0%. An increase in white cell and neutrophil counts from baseline to week 3-4 was observed. Only small variations were observed after this time, but the counts remained higher than the initial values. These changes were statistically significant in the white cell count: One-way repeated ANOVA with Greenhouse-Geisser correction F (11.47, 37) = 2.114 (P= .011); and in neutrophils: One-way repeated ANOVA with Greenhouse-Geisser correction F (10.3, 37)=3.312 (P=.0002), and MANOVA F (18, 37)=2.693 (P=.005), ŋ2P=0.567. The influence of concomitant drugs (lithium, valproic and biperiden) was not significant on the overall increase found in white cells or neutrophils (MANOVA)

Pulmonary Infections in the Elderly Lead to Impaired Neutrophil Targeting, Which Is Improved by Simvastatin.

RATIONALE: Dysregulated neutrophil functions with age and sepsis are described. Statins are associated with improved infection survival in some observational studies, but trials in critically ill patients have not shown benefit. Statins also alter neutrophil responses in vitro. OBJECTIVES: To assess neutrophil migratory accuracy with age during respiratory infections and determine if and how a statin intervention could alter these blunted responses. METHODS: The migratory accuracy of blood neutrophils from young (aged <35 yr) and old (aged >60 yr) patients in health and during a lower respiratory tract infection, community-acquired pneumonia, and pneumonia associated with sepsis was assessed with and without simvastatin. In vitro results were confirmed in a double-blind randomized clinical trial in healthy elders. Cell adhesion markers were assessed. MEASUREMENTS AND MAIN RESULTS: In vitro neutrophil migratory accuracy in the elderly deteriorated as the severity of the infectious pulmonary insult increased, without recovery at 6 weeks. Simvastatin rescued neutrophil migration with age and during mild to moderate infection, at high dose in older adults, but not during more severe sepsis. Confirming in vitro results, high-dose (80-mg) simvastatin improved neutrophil migratory accuracy without impeding other neutrophil functions in a double-blind randomized clinical trial in healthy elders. Simvastatin modified surface adhesion molecule expression and activity, facilitating accurate migration in the elderly. CONCLUSIONS: Infections in older adults are associated with prolonged, impaired neutrophil migration, potentially contributing to poor outcomes. Statins improve neutrophil migration in vivo in health and in vitro in milder infective events, but not in severe sepsis, supporting their potential utility as an early intervention during pulmonary infections. Clinical trial registered with www.clinicaltrialsregister.eu (2011-002082-38).

BAL neutrophilia in azithromycin-treated lung transplant recipients: Clinical significance.

BACKGROUND: Azithromycin decreases airway neutrophilia and can prevent chronic lung allograft dysfunction (CLAD) after lung transplantation (LTx). It also can be used to treat lymphocytic bronchiolitis, as it decreases the submucosal infiltrating IL-17 positive lymphocytes. Some patients, while receiving azithromycin, (re)develop increased airway neutrophilia, which we hypothesize to result in worse outcome and to be regulated by an IL-17-independent mechanism. METHODS: LTx recipients, transplanted between 2001 and 2012, were investigated and categorized in a study group of patients with increased broncho-alveolar lavage (BAL) neutrophilia (≥15%) and a matched control group with low BAL neutrophilia (<15%), both groups while already being on azithromycin treatment. CLAD-free and overall survival were compared between groups. Cell differentials and 33 proteins in BAL were analyzed to identify underlying mechanisms. RESULTS: The study group (n=72) demonstrated a significantly lower CLAD-free (p=0.015) and overall survival (p=0.041) compared to the control group (n=37). Absolute BAL neutrophils and eosinophils were increased in the study group, which was paralleled by elevated inflammatory cytokines (IL-1ß/IL-1Ra, IL-4 and IL-6) and chemokines (CXCL8/IL-8, CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1ß, CCL11/eotaxin) concentrations compared to the control group (all p<0.05). CONCLUSION: Patients with elevated airway neutrophilia despite azithromycin, experience worse CLAD-free and overall survival. In these patients, IL-1ß might play a central role giving rise to neutrophils, eosinophils, macrophages and B-cells. This provides an opportunity to further investigate the modulation of this pathway.

Riparin A, a compound from Aniba riparia, attenuate the inflammatory response by modulation of neutrophil migration.

Inflammation is a local tissue response to attacks characterized by vascular and cellular events, including intense oxidative stress. Riparin A, a compound obtained from Aniba riparia, has been shown to have antioxidant activity and cytotoxicity in vitro. This study was aimed at evaluating the anti-inflammatory effect of riparin A against acute inflammation. The results of our evaluations in various experimental models indicated that riparin A reduced paw edema induced by carrageenan, compound 48/80, histamine, and serotonin. Furthermore, it decreased leukocyte and neutrophil counts, myeloperoxidase activity, thiobarbituric acid reactive substance (TBARS) levels, and cytokine (tumor necrosis factor-α and interleukin-1ß) levels increased by carrageenan-induced peritonitis, and reversed glutathione levels. Riparin A also reduced carrageenan-induced adhesion and rolling of leukocytes on epithelial cells and did not produce gastric-damage as compared with indomethacin. In conclusion, the data show that riparin A reduces inflammatory response by inhibiting vascular and cellular events, modulating neutrophil migration, inhibiting proinflammatory cytokine production, and reducing oxidative stress.

A case of refractory chronic neutrophilic pustular folliculitis treated with adalimumab.

Neutrophilic folliculitis is an often overlooked chronic condition characterized by a monomorphic eruption of "sterile" papulopustules. Neutrophilic folliculitis is often refractory to conventional treatment with topical and systemic antibiotics or isotretinoin. We report a case of severe pustular neutrophilic folliculitis successfully treated with the tumor necrosis factor-alpha inhibitor adalimumab.

Fucosylated chondroitin sulfates from the body wall of the sea cucumber Holothuria forskali: conformation, selectin binding, and biological activity.

Fucosylated chondroitin sulfate (fCS) extracted from the sea cucumber Holothuria forskali is composed of the following repeating trisaccharide unit: → 3)GalNAcß4,6S(1 → 4) [FucαX(1 → 3)]GlcAß(1 →, where X stands for different sulfation patterns of fucose (X = 3,4S (46%), 2,4S (39%), and 4S (15%)). As revealed by NMR and molecular dynamics simulations, the fCS repeating unit adopts a conformation similar to that of the Le(x) blood group determinant, bringing several sulfate groups into close proximity and creating large negative patches distributed along the helical skeleton of the CS backbone. This may explain the high affinity of fCS oligosaccharides for L- and P-selectins as determined by microarray binding of fCS oligosaccharides prepared by Cu(2+)-catalyzed Fenton-type and photochemical depolymerization. No binding to E-selectin was observed. fCS poly- and oligosaccharides display low cytotoxicity in vitro, inhibit human neutrophil elastase activity, and inhibit the migration of neutrophils through an endothelial cell layer in vitro. Although the polysaccharide showed some anti-coagulant activity, small oligosaccharide fCS fragments had much reduced anticoagulant properties, with activity mainly via heparin cofactor II. The fCS polysaccharides showed prekallikrein activation comparable with dextran sulfate, whereas the fCS oligosaccharides caused almost no effect. The H. forskali fCS oligosaccharides were also tested in a mouse peritoneal inflammation model, where they caused a reduction in neutrophil infiltration. Overall, the data presented support the action of fCS as an inhibitor of selectin interactions, which play vital roles in inflammation and metastasis progression. Future studies of fCS-selectin interaction using fCS fragments or their mimetics may open new avenues for therapeutic intervention.

Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence.

Immunosenescence is the functional deterioration of the immune system during natural aging. Despite increased susceptibility to bacterial infections in older adults, age-associated changes to neutrophil responses are only partially understood, and neutrophil migration has not been characterized in detail. Here we describe reduced chemotaxis but preserved chemokinesis toward a range of inflammatory stimuli in migrating neutrophils isolated from healthy older subjects. Cross-sectional data indicate that migratory behavior changes in the sixth decade of life. Crucially, aberrant migration may increase "bystander" tissue damage and heighten inflammation as a result of excess proteinase release during inaccurate chemotaxis, as well as reducing pathogen clearance. We show evidence of increased neutrophil proteinase activity in older adults, namely, raised levels of neutrophil proteinase substrate-derived peptides and evidence of primary granule release, associated with increased systemic inflammation. Inaccurate migration was causally associated with increased constitutive phosphoinositide 3-kinase (PI3K) signaling; untreated neutrophils from old donors demonstrated significant PI3K activation compared with cells from young donors. PI3K-blocking strategies, specifically inhibition of PI3Kγ or PI3Kδ, restored neutrophil migratory accuracy, whereas SHIP1 inhibition worsened migratory flaws. Targeting PI3K signaling may therefore offer a new strategy in improving neutrophil functions during infections and reduce inappropriate inflammation in older patients.

Carvacryl acetate, a derivative of carvacrol, reduces nociceptive and inflammatory response in mice.

AIMS: The present study aimed to investigate the potential anti-inflammatory and anti-nociceptive effects of carvacryl acetate, a derivative of carvacrol, in mice. MAIN METHODS: The anti-inflammatory activity was evaluated using various phlogistic agents that induce paw edema, peritonitis model, myeloperoxidase (MPO) activity, pro and anti-inflammatory cytokine levels. Evaluation of antinociceptive activity was conducted through acetic acid-induced writhing, hot plate test, formalin test, capsaicin and glutamate tests, as well as evaluation of motor performance on rotarod test. KEY FINDINGS: Pretreatment of mice with carvacryl acetate (75 mg/kg) significantly reduced carrageenan-induced paw edema (P<0.05) when compared to vehicle-treated group. Likewise, carvacryl acetate (75 mg/kg) strongly inhibited edema induced by histamine, serotonin, prostaglandin E2 and compound 48/80. In the peritonitis model, carvacryl acetate significantly decreased total and differential leukocyte counts, and reduced levels of myeloperoxidase and interleukin-1 beta (IL-1ß) in the peritoneal exudate. The levels of IL-10, an anti-inflammatory cytokine, were enhanced by carvacryl acetate. Pretreatment with carvacryl acetate also decreased the number of acetic acid-induced writhing, increased the latency time of the animals on the hot plate and decreased paw licking time in the formalin, capsaicin and glutamate tests. The pretreatment with naloxone did not reverse the carvacryl acetate-mediated nociceptive effect. SIGNIFICANCE: In conclusion, the current study demonstrated that carvacryl acetate exhibited anti-inflammatory activity in mice by reducing inflammatory mediators, neutrophil migration and cytokine concentration, and anti-nociceptive activity due to the involvement of capsaicin and glutamate pathways.

Evaluation of the therapeutic index of a novel phosphodiesterase 4B-selective inhibitor over phosphodiesterase 4D in mice.

Phosphodiesterase 4 (PDE4) inhibitors have been developed for the treatment of pulmonary inflammatory diseases, but their clinical use was dose-limited by mainly gastric adverse effects. Recent studies suggested PDE4B-selective inhibitors over PDE4D are supposed to display a wider therapeutic index than subtype non-selective PDE4 inhibitors such as roflumilast. Compound A was identified as an orally active PDE4B-selective inhibitor over PDE4D both in humans (80-fold selective) and mice (29-fold selective). In this study, the therapeutic effects of compound A and roflumilast were evaluated on lipopolysaccaride (LPS) injection-induced plasma TNF-α elevation and on LPS inhalation-induced pulmonary neutrophilia in mice. The inhibitory effect on gastric emptying in mice was evaluated as a gastric adverse effect. The therapeutic index for TNF-α production (TI(TNF) = ID50 in gastric emptying / ID50 in LPS injection-induced plasma TNF-α elevation) of compound A was larger than roflumilast (9.0 and 0.2, respectively), whereas the therapeutic index for pulmonary neutrophilia (TI(Neu) = ID50 in gastric emptying / ID50 in LPS inhalation-induced pulmonary neutrophilia) of compound A was comparable to roflumilast (1.0 and 0.5, respectively). In conclusion, the TI(Neu) of compound A was not superior compared to that of roflumilast in spite of its high selectivity for PDE4B over PDE4D in mice.

Toll-like receptor 3 stimulation causes corticosteroid-refractory airway neutrophilia and hyperresponsiveness in mice.

BACKGROUND: RNA virus infections, such as rhinovirus and respiratory syncytial virus, induce exacerbations in patients with COPD and asthma, and the inflammation is corticosteroid refractory. The main aim of this study is to establish a murine model induced by a Toll-like receptor 3 (TLR3) agonist, an RNA virus mimic, and investigate the response to corticosteroid. METHODS: A/J mice were given polyinosinic-polycytidylic acid (poly[I:C]), a TLR3 agonist, intranasally, in the presence or absence of cigarette smoke exposure. Inflammatory cell accumulation and C-X-C motif chemokine (CXCL) 1, interferon (IFN), and CXCL10 production in BAL fluid (BALF) were determined by flow cytometry and enzyme-linked immunosorbent assay, respectively, and airway hyperresponsiveness (AHR) to histamine/methacholine was determined by a two-chambered, double-flow plethysmography system. BALB/c and C57BL/6J mice were also used for comparisons. RESULTS: Intranasal treatment of poly(I:C) significantly induced airway neutrophilia; production of CXCL1, IFN-ß, and CXCL10; and necrotic cell accumulation in BALF. It also increased airway responsiveness to histamine or methacholine inhalation. This poly(I:C)-dependent airway inflammation and AHR was not inhibited by the corticosteroid fluticasone propionate (FP) (up to 0.5 mg/mL intranasal), although FP strongly inhibited lipopolysaccharide (TLR4 agonist)-induced airway neutrophilia. Furthermore, cigarette smoke exposure significantly increased TLR3 expression in murine lung tissue and exacerbated poly(I:C)-induced neutrophilia and AHR. CONCLUSIONS: These results suggest that TLR3 stimulation is involved in corticosteroid-refractory airway inflammation in lung, which is enhanced by cigarette smoking, and this may provide a model for understanding virus-induced exacerbations in COPD and their therapy.

Evaluation of antiasthmatic activity of Clitoria ternatea L. roots.

AIM OF STUDY: Clitoria ternatea L. (Family: Fabaceae) is being used in traditional medicine for the treatment of severe bronchitis and asthma. So the aim of study was to evaluate antiasthmatic activity of ethanol extract of Clitoria ternatea roots. MATERIALS AND METHODS: In the present study ethanol extract of Clitoria ternatea root (ECTR) was evaluated for preliminary phytochemical screening, acute toxicity studies and antiasthmatic activity using milk induced leucocytosis and eosinophilia in mice, egg albumin induced mast cell degranulations in rats and passive cutaneous anaphylaxis in rats at doses (100-150 mg/kg ip). RESULTS: The results of present investigation showed that the LD(50) of ECTR is more than 1,300 mg/kg. ECTR significantly decreases milk induced leucocytosis and eosinophilia, protects egg albumin induced degranulations of mast cells in mice and inhibits area of blue dye leakage in passive cutaneous anaphylaxis in rats at (100-150 mg/kg, i.p.). Phytochemical studies observed the presence of steroids, saponin, flavonoids, and glycosides. CONCLUSION: The present investigation concludes that the antiasthmatic activity of ECTR may be due to the presence of flavonoids or saponins.