pyrimidinones and Asthma

Topics: Administration, Inhalation; Adult; Androstadienes; Antiviral Agents; Asthma; Biological Availability; Cushing Syndrome; Cytochrome P-450 Enzyme Inhibitors; Drug Therapy, Combination; Fluticasone; Glucocorticoids; HIV Infections; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir

Topics: Adolescent; Age Factors; Albuterol; Androstadienes; Anticonvulsants; Asthma; Atovaquone; Attention Deficit Disorder with Hyperactivity; Beclomethasone; Carbamazepine; Child; Delayed-Action Preparations; Diabetes Mellitus, Type 1; Drug Approval; Drug Combinations; Drug Delivery Systems; Drug Therapy; Epilepsies, Partial; Fluticasone-Salmeterol Drug Combination; HIV Protease Inhibitors; Humans; Insulin; Insulin Glargine; Insulin, Long-Acting; Lopinavir; Methylphenidate; Naphthoquinones; Nebulizers and Vaporizers; Oxcarbazepine; Pediatrics; Proguanil; Pyrimidinones; Ritonavir; United States

This study aimed to investigate the dose-response and pharmacology of a range of single doses of nebulised ensifentrine (RPL554), an inhaled dual phosphodiesterase (PDE) 3/4 inhibitor in patients with asthma.. In this randomised, placebo-controlled, double-blind crossover study, patients received single nebulised doses of ensifentrine 0.4, 1.5, 6 and 24 mg, salbutamol 2.5 and 7.5 mg, and placebo. Eligible patients were adults with asthma, pre-bronchodilator forced expiratory volume in 1 s (FEV. A total of 29 patients were randomised, with 25 (89%) completing the study. For the two co-primary endpoints there was a clear ensifentrine dose-response relationship, with all treatments superior to placebo (p < 0.001). There was no relationship between the ensifentrine dose and AE incidence or blood pressure. Ensifentrine 0.4, 1.5 and 6 mg had significantly lower effects than both salbutamol doses on pulse and heart rates. Ensifentrine did not impact potassium, whereas there was a was a dose-related reduction for salbutamol. Inhalation of ensifentrine resulted in a dose-related increase in plasma exposure.. Single-dose ensifentrine demonstrated dose-dependent bronchodilation, and was as effective as a therapeutic dose of nebulised salbutamol. All ensifentrine doses were similarly well tolerated, and did not show the characteristic β

Topics: Administration, Inhalation; Adult; Aged; Albuterol; Asthma; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Isoquinolines; Male; Middle Aged; Nebulizers and Vaporizers; Phosphodiesterase 3 Inhibitors; Pyrimidinones

Many patients with asthma or chronic obstructive pulmonary disease (COPD) routinely receive a combination of an inhaled bronchodilator and anti-inflammatory glucocorticosteroid, but those with severe disease often respond poorly to these classes of drug. We assessed the efficacy and safety of a novel inhaled dual phosphodiesterase 3 (PDE3) and PDE4 inhibitor, RPL554 for its ability to act as a bronchodilator and anti-inflammatory drug.. Between February, 2009, and January, 2013, we undertook four proof-of-concept clinical trials in the Netherlands, Italy, and the UK. Nebulised RPL554 was examined in study 1 for safety in 18 healthy men who were randomly assigned (1:1:1) to receive an inhaled dose of RPL554 (0·003 mg/kg or 0·009 mg/kg) or placebo by a computer-generated randomisation table. Subsequently, six non-smoking men with mild allergic asthma received single doses of RPL554 (three received 0·009 mg/kg and three received 0·018 mg/kg) in an open-label, adaptive study, and then ten men with mild allergic asthma were randomly assigned to receive placebo or RPL554 (0·018 mg/kg) by a computer-generated randomisation table for an assessment of safety, bronchodilation, and bronchoprotection. Study 2 examined the reproducibility of the bronchodilator response to a daily dose of nebulised RPL554 (0·018 mg/kg) for 6 consecutive days in a single-blind (patients masked), placebo-controlled study in 12 men with clinically stable asthma. The safety and bronchodilator effect of RPL554 (0·018 mg/kg) was assessed in study 3, an open-label, placebo-controlled crossover trial, in 12 men with mild-to-moderate COPD. In study 4, a placebo-controlled crossover trial, the effect of RPL554 (0·018 mg/kg) on lipopolysaccharide-induced inflammatory cell infiltration in induced sputum was investigated in 21 healthy men. In studies 3 and 4, randomisation was done by computer-generated permutation with a block size of two for study 3 and four for study 4. Unless otherwise stated, participants and clinicians were masked to treatment assignment. Analyses were by intention to treat. All trials were registered with EudraCT, numbers 2008-005048-17, 2011-001698-22, 2010-023573-18, and 2012-000742-34.. Safety was a primary endpoint of studies 1 and 3 and a secondary endpoint of studies 2 and 4. Overall, RPL554 was well tolerated, and adverse events were generally mild and of equal frequency between placebo and active treatment groups. Efficacy was a primary endpoint of study 2 and a secondary endpoint of studies 1 and 3. Study 1 measured change in forced expiratory volume in 1 s (FEV1) and provocative concentration of methacholine causing a 20% fall in FEV1 (PC20MCh) in participants with asthma. RPL554 produced rapid bronchodilation in patients with asthma with an FEV1 increase at 1 h of 520 mL (95% CI 320-720; p<0·0001), which was a 14% increase from placebo, and increased the PC20MCh by 1·5 doubling doses (95% CI 0·63-2·28; p=0·004) compared with placebo. The primary endpoint of study 2 was maximum FEV1 reached during 6 h after dosing with RPL554 in patients with asthma. RPL554 produced a similar maximum mean increase in FEV1 from placebo on day 1 (555 mL, 95% CI 442-668), day 3 (505 mL, 392-618), and day 6 (485 mL, 371-598; overall p<0·0001). A secondary endpoint of study 3 (patients with COPD) was the increase from baseline in FEV1. RPL554 produced bronchodilation with a mean maximum FEV1 increase of 17·2% (SE 5·2). In healthy individuals (study 4), the primary endpoint was percentage change in neutrophil counts in induced sputum 6 h after lipopolysaccharide challenge. RPL554 (0·018 mg/kg) did not significantly reduce the percentage of neutrophils in sputum (80·3% in the RPL554 group vs 84·2% in the placebo group; difference -3·9%, 95% CI -9·4 to 1·6, p=0·15), since RPL554 significantly reduced neutrophils (p=0·002) and total cells (p=0·002) to a similar degree.. In four exploratory studies, inhaled RPL554 is an effective and well tolerated bronchodilator, bronchoprotector, and anti-inflammatory drug and further studies will establish the full potential of this new drug for the treatment of patients with COPD or asthma.. Verona Pharma.

Topics: Administration, Inhalation; Adult; Aged; Asthma; Female; Follow-Up Studies; Forced Expiratory Volume; Healthy Volunteers; Humans; Isoquinolines; Male; Middle Aged; Nebulizers and Vaporizers; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 4 Inhibitors; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Pyrimidinones; Single-Blind Method; Treatment Outcome; Young Adult

Pemirolast is a new oral, nonbronchodilator antiallergy medication that is being evaluated for the therapy of asthma. In this multicenter, double-blind, randomized study, 96 patients with mild asthma received pemirolast, 50 mg (n = 34); pemirolast, 25 mg (n = 31); or placebo (n = 31) BID for 6 weeks. Patients were evaluated weekly at the research centers; they maintained daily symptom diaries and measured peak expiratory flow rates twice a day. Methacholine challenge was performed at the start and end of the study. Results with pemirolast, 50 mg BID, showed statistically significant decrease in nocturnal symptoms (P = .02), in composite symptom scores (P = .02) and in bronchodilator use (P = .05) when compared with placebo. There were no statistically significant differences between treatments in pulmonary function tests or in methacholine challenge sensitivity. Pemirolast, 25 mg BID, did not differ from placebo. There were no significant adverse effects. Pemirolast, 50 mg BID, demonstrated sufficient antiasthma activity to warrant further studies in patients with more severe asthma and with higher doses.

Topics: Administration, Oral; Adolescent; Adult; Aged; Asthma; Bronchial Spasm; Chronic Disease; Double-Blind Method; Forced Expiratory Volume; Histamine Antagonists; Humans; Middle Aged; Placebos; Pyridines; Pyrimidinones

Asthmatic airways feature increased ASM mass that is largely attributable to hyperplasia, and which potentially contributes to excessive airway narrowing. T cells induce ASMC proliferation via contact-dependent mechanisms in vitro that may have importance for asthmatic ASM growth, as CD4+ T cells infiltrate ASM bundles in asthmatic human airways. In this study, we used an in vitro migration assay to investigate the pathways responsible for the trafficking of human CD4+ T cells to ASM. ASMCs induced chemotaxis of activated CD4+ T cells, which was inhibited by the CXCR3 antagonist AMG487 and neutralizing antibodies against its ligands CXCL10 and 11, but not CCR3 or CCR5 antagonists. CXCR3 expression was upregulated among all T cells following anti-CD3/CD28-activation. CD4+ T cells upregulated CXCL9, 10, and 11 expression in ASMCs in an IFN-γ/STAT1-dependent manner. Disruption of IFN-γ-signaling resulted in reduced T cell migration, along with the inhibition of CD4+ T cell-mediated STAT1 activation and CXCR3 ligand secretion by ASMCs. ASMCs derived from healthy and asthmatic donors demonstrated similar T cell-recruiting capacities. In vivo CXCL10 and 11 expression by asthmatic ASM was confirmed by immunostaining. We conclude that the CXCL10/11-CXCR3 axis causes CD4+ T cell recruitment to ASM that is amplified by T cell-derived IFN-γ.

Topics: Acetamides; Antibodies, Neutralizing; Asthma; CD4-Positive T-Lymphocytes; Cells, Cultured; Chemokine CXCL10; Chemokine CXCL11; Humans; Interferon-gamma; Muscle, Smooth; Pyrimidinones; Receptors, CXCR3

Ensifentrine (RPL554), an inhaled 'bifunctional' dual phosphodiesterase 3/4 inhibitor that exhibits both bronchodilator and anti-inflammatory activities, provides a new option in the treatment of chronic obstructive pulmonary disease (COPD) and other inflammatory airway diseases that are under clinical development. Ensifentrine appears to be initially under development for the treatment of COPD although it is not yet clear whether it should be understood as an add-on therapy in patients for the treatment of acute exacerbations of COPD or for the regular maintenance treatment of patients either alone, or on top of existing drug classes.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents; Asthma; Bronchodilator Agents; Humans; Isoquinolines; Patents as Topic; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Pyrimidinones

Aberrant activation of β-catenin signaling by both WNT-dependent and WNT-independent pathways has been demonstrated in asthmatic airways, which is thought to contribute critically in remodeling of the airways. Yet, the exact role of β-catenin in asthma is very poorly defined. As we have previously reported abnormal expression of β-catenin in a toluene diisocyanate (TDI)-induced asthma model, in this study, we evaluated the therapeutic efficacy of two small molecules XAV-939 and ICG-001 in TDI-asthmatic male BALB/c mice, which selectively block β-catenin-mediated transcription.. Male BALB/c mice were sensitized and challenged with TDI to generate a chemically induced asthma model. Inhibitors of β-catenin, XAV-939, and ICG-001 were respectively given to the mice through intraperitoneally injection.. TDI exposure led to a significantly increased activity of β-catenin, which was then confirmed by a luciferase assay in 16HBE transfected with the TOPFlash reporter plasmid. Treatment with either XAV-939 or ICG-001 effectively inhibited activation of β-catenin and downregulated mRNA expression of β-catenin-targeted genes in TDI-asthmatic mice, paralleled by dramatically attenuated TDI-induced hyperresponsiveness and inflammation of the airway, alleviated airway goblet cell metaplasia and collagen deposition, decreased Th2 inflammation, as well as lower levels of TGFβ1, VEGF, HMGB1, and IL-1β.. The results showed that β-catenin is a principal mediator of TDI-induced asthma, proposing β-catenin as a promising therapeutic target in asthma.

Topics: Airway Remodeling; Animals; Anti-Asthmatic Agents; Asthma; beta Catenin; Biomarkers; Bridged Bicyclo Compounds, Heterocyclic; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Gene Expression Regulation; Heterocyclic Compounds, 3-Ring; Immunoglobulin E; Immunohistochemistry; Lymphocytes; Male; Mice; Molecular Targeted Therapy; Pyrimidinones; Signal Transduction; Toluene 2,4-Diisocyanate

Cystic fibrosis (CF), a genetic disease caused by mutations in the CFTR gene, is a life-limiting disease characterized by chronic bacterial airway infection and severe inflammation. Some CFTR mutants have reduced responsiveness to cAMP/PKA signaling; hence, pharmacological agents that elevate intracellular cAMP are potentially useful for the treatment of CF. By inhibiting cAMP breakdown, phosphodiesterase (PDE) inhibitors stimulate CFTR in vitro and in vivo. Here, we demonstrate that PDE inhibition by RPL554, a drug that has been shown to cause bronchodilation in asthma and chronic obstructive pulmonary disease (COPD) patients, stimulates CFTR-dependent ion secretion across bronchial epithelial cells isolated from patients carrying the R117H/F508del CF genotype. RPL554-induced CFTR activity was further increased by the potentiator VX-770, suggesting an additional benefit by the drug combination. RPL554 also increased cilia beat frequency in primary human bronchial epithelial cells. The results indicate RPL554 may increase mucociliary clearance through stimulation of CFTR and increasing ciliary beat frequency and thus could provide a novel therapeutic option for CF.

Topics: Asthma; Cells, Cultured; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Humans; Ion Transport; Isoquinolines; Mucociliary Clearance; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Pyrimidinones

Airway smooth muscle cell (ASMC) phenotypic modulation is one of the key factors contributing to asthma. Temperature changes may induce asthma, and these changes are known to be related to the temperature-sensitive transient receptor potential channels (TS-TRPs). The present study was designed to investigate the cellular functions of cold-sensitive channels, TRPM8 and TRPA1, in the phenotypic modulation of ASMCs.. A rat asthma model was constructed and the expression of TS-TRPs in ASM was tested. Using the agonists and antagonists for both TRPM8 and TRPA1, the effects of cold-sensitive channels on the phenotypic modulation of ASMCs were evaluated by measurement of contractile protein expression and cell proliferation and migration. Signaling pathways and matrix metalloproteinase-2 (MMP-2) activity were assayed with Western blotting and gelatin zymography.. TRPM8 and TRPA1 were decreased in the ASM of the rat asthma model. Icilin and menthol, agonists for TRPM8 and TRPA1, inhibited ASMC proliferation and migration induced by fetal bovine serum (FBS) or platelet-derived growth factor (PDGF). Moreover, icilin reversed the FBS-induced inhibition of the expression of contractile phenotype markers, smooth muscle α-actin, and SM22α. Icilin also antagonized the activation of p38 and MMP-2 and the repression of p21 caused by FBS.. Our findings show, for the first time, that the activation of TRPM8 and TRPA1 inhibits ASMC proliferative phenotype. These data suggest that TRPM8 and TRPA1 agonists may be promising new therapies for asthma.

Topics: Actins; Airway Remodeling; Animals; Asthma; Bronchi; Calcium Channel Agonists; Cell Movement; Cell Proliferation; Cold Temperature; Disease Models, Animal; Female; Matrix Metalloproteinase 2; Menthol; Microfilament Proteins; Muscle Contraction; Muscle Proteins; Myocytes, Smooth Muscle; p21-Activated Kinases; p38 Mitogen-Activated Protein Kinases; Phenotype; Platelet-Derived Growth Factor; Pyrimidinones; Rats; Rats, Sprague-Dawley; Signal Transduction; Trachea; TRPA1 Cation Channel; TRPM Cation Channels

Asthma is a heterogeneous chronic inflammatory disease, characterized by the development of structural changes (airway remodelling). β-catenin, a transcriptional co-activator, is fundamentally involved in airway smooth muscle growth and may be a potential target in the treatment of airway smooth muscle remodelling.. We assessed the ability of small-molecule compounds that selectively target β-catenin breakdown or its interactions with transcriptional co-activators to inhibit airway smooth muscle remodelling in vitro and in vivo.. ICG-001, a small-molecule compound that inhibits the β-catenin/CREB-binding protein (CBP) interaction, strongly and dose-dependently inhibited serum-induced smooth muscle growth and TGFβ1-induced production of extracellular matrix components in vitro. Inhibition of β-catenin/p300 interactions using IQ-1 or inhibition of tankyrase 1/2 using XAV-939 had considerably less effect. In a mouse model of allergic asthma, β-catenin expression in the smooth muscle layer was found to be unaltered in control versus ovalbumin-treated animals, a pattern that was found to be similar in smooth muscle within biopsies taken from asthmatic and non-asthmatic donors. However, β-catenin target gene expression was highly increased in response to ovalbumin; this effect was prevented by topical treatment with ICG-001. Interestingly, ICG-001 dose-dependently reduced airway smooth thickness after repeated ovalbumin challenge, but had no effect on the deposition of collagen around the airways, mucus secretion or eosinophil infiltration.. Together, our findings highlight the importance of β-catenin/CBP signalling in the airways and suggest ICG-001 may be a new therapeutic approach to treat airway smooth muscle remodelling in asthma.

Topics: Airway Remodeling; Animals; Anti-Asthmatic Agents; Asthma; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; CREB-Binding Protein; Disease Models, Animal; Dose-Response Relationship, Drug; Extracellular Matrix; Female; Gene Expression Regulation; Heterocyclic Compounds, 3-Ring; Humans; Mice; Mice, Inbred BALB C; Muscle, Smooth; Ovalbumin; Pyrimidinones

The epithelium of asthmatics is characterized by reduced expression of E-cadherin and increased expression of the basal cell markers ck-5 and p63 that is indicative of a relatively undifferentiated repairing epithelium. This phenotype correlates with increased proliferation, compromised wound healing and an enhanced capacity to undergo epithelial-mesenchymal transition (EMT). The transcription factor β-catenin plays a vital role in epithelial cell differentiation and regeneration, depending on the co-factor recruited. Transcriptional programs driven by the β-catenin/CBP axis are critical for maintaining an undifferentiated and proliferative state, whereas the β-catenin/p300 axis is associated with cell differentiation. We hypothesized that disrupting the β-catenin/CBP signaling axis would promote epithelial differentiation and inhibit EMT. We treated monolayer cultures of human airway epithelial cells with TGFβ1 in the presence or absence of the selective small molecule ICG-001 to inhibit β-catenin/CBP signaling. We used western blots to assess expression of an EMT signature, CBP, p300, β-catenin, fibronectin and ITGβ1 and scratch wound assays to assess epithelial cell migration. Snai-1 and -2 expressions were determined using q-PCR. Exposure to TGFβ1 induced EMT, characterized by reduced E-cadherin expression with increased expression of α-smooth muscle actin and EDA-fibronectin. Either co-treatment or therapeutic administration of ICG-001 completely inhibited TGFβ1-induced EMT. ICG-001 also reduced the expression of ck-5 and -19 independent of TGFβ1. Exposure to ICG-001 significantly inhibited epithelial cell proliferation and migration, coincident with a down regulation of ITGβ1 and fibronectin expression. These data support our hypothesis that modulating the β-catenin/CBP signaling axis plays a key role in epithelial plasticity and function.

Topics: Actins; Asthma; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Cell Differentiation; Cell Movement; Cell Proliferation; E1A-Associated p300 Protein; Epithelial Cells; Epithelial-Mesenchymal Transition; Fibronectins; Gene Expression Regulation; Humans; Keratin-19; Keratin-5; Peptide Fragments; Primary Cell Culture; Pyrimidinones; Respiratory Mucosa; Sialoglycoproteins; Signal Transduction; Snail Family Transcription Factors; Transcription Factors; Transforming Growth Factor beta1

Topics: Asthma; Female; Humans; Isoquinolines; Male; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Pyrimidinones

The ADP-ribosyl cyclase activity of CD38 generates cyclic ADP-ribose, a Ca(2+)-mobilizing agent. In human airway smooth muscle (HASM) cells, TNF-α mediates CD38 expression through mitogen-activated protein kinases and NF-κB and AP-1. The phosphatidylinositol-3 kinase/Akt (PI3K/Akt) pathway is involved in TNF-α signaling and contributes to airway hyperresponsiveness and airway remodeling. We hypothesized that PI3Ks mediate CD38 expression and are involved in the differential induction of CD38 by TNF-α in asthmatic HASM cells. HASM cells were treated with pan-PI3K inhibitors (LY294002 or wortmannin) or class I-selective (GDC0941) or isoform-selective PI3K inhibitors (p110α-PIK-75 and p110β-TGX-221) with or without TNF-α. HASM cells were transfected with a catalytically active form of PI3K or phosphatase and tensin homolog (PTEN) or nontargeting or p110 isoform-targeting siRNAs before TNF-α exposure. CD38 expression and activation of Akt, NF-κB, and AP-1 were determined. LY294002 and wortmannin inhibited TNF-α-induced Akt activation, whereas only LY294002 inhibited CD38 expression. P110 expression caused Akt activation and basal and TNF-α-induced CD38 expression, whereas PTEN expression attenuated Akt activation and CD38 expression. Expression levels of p110 isoforms α, β, and δ were comparable in nonasthmatic and asthmatic HASM cells. Silencing of p110α or -δ, but not p110β, resulted in comparable attenuation of TNF-α-induced CD38 expression in asthmatic and nonasthmatic cells. NF-κB and AP-1 activation were unaltered by the PI3K inhibitors. In HASM cells, regulation of CD38 expression occurs by specific class I PI3K isoforms, independent of NF-κB or AP-1 activation, and PI3K signaling may not be involved in the differential elevation of CD38 in asthmatic HASM cells.

Topics: ADP-ribosyl Cyclase 1; Asthma; Cells, Cultured; Chromones; Class Ia Phosphatidylinositol 3-Kinase; Enzyme Activation; Gene Expression Regulation; Gene Knockdown Techniques; Humans; Isoenzymes; Membrane Glycoproteins; Morpholines; Myocytes, Smooth Muscle; NF-kappa B; Phosphoinositide-3 Kinase Inhibitors; Primary Cell Culture; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Pyrimidinones; Respiratory System; RNA Interference; Signal Transduction; Transcription Factor AP-1; Tumor Necrosis Factor-alpha

To investigate the development of airway hyperresponsiveness in infantile guinea pigs, animals (10 days old) were immunized twice and challenged by inhalation of 1% ovalbumin for 10 min with 7 days intervals. Similar to adult guinea pigs, infantile ones developed an increased airway responsiveness to acetylcholine 24 hr after antigen challenge. There was a marked increase in the number of total leukocytes, eosinophils and lymphocytes in bronchoalveolar lavage fluid (BALF). Suplatast tosilate (suplatast) and pemirolast potassium (pemirolast) given orally throughout the experiments suppressed the development of airway hyperresponsiveness in infantile animals. They showed similar potency in the suppression of eosinophil accumulation in BALF and lung tissue, while suplatast inhibited lymphocyte accumulation stronger than pemirolast. Collectively, the present model of airway hyperresponsiveness in infantile guinea pigs may be useful in predicting the efficacy of antiallergic agents in the treatment of asthmatic children.

Topics: Animals; Anti-Allergic Agents; Antigens; Arylsulfonates; Asthma; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Guinea Pigs; Histamine Antagonists; Leukocyte Count; Male; Ovalbumin; Pyridines; Pyrimidinones; Respiratory Hypersensitivity; Sulfonium Compounds

Although acyclovir (9-(2-hydroxyethoxymethyl) guanine) is an antiviral drug that inhibits DNA polymerase of herpes virus, we have had the experience of an asthmatic patient's peak flow rate being improved by oral administration of acyclovir.. The aim of this experiment is whether acyclovir has anti-asthma effects using an asthma model in guinea-pigs.. The airway response was induced by a single inhalation of calcium ionophore A23187 (2 mg/mL). The airway obstruction was estimated by the ratio of expiration to inspiration time (E/I). The peribronchial eosinophil infiltration and eosinophil influx into bronchoalveolar lavage (BAL) fluid 7 h after the inhalation were also examined. To assess the effects of acyclovir (1, 10, and 100 mg/kg), aminophylline (20 mg/kg) and pemirolast potassium (TBX, 20 mg/kg) on A23187-induced asthmatic response, the drugs were intraperitoneally administered before the inhalation.. The immediate airway obstruction was significantly suppressed by acyclovir (10 mg/kg) and aminophylline, whereas different doses of acyclovir (1 and 100 mg/kg) and TBX showed only a small inhibitory effect on the airway obstruction. On the other hand, the peribronchial eosinophilia was most successfully inhibited by TBX. Acyclovir (10 mg/kg) and aminophylline also suppressed the eosinophilia significantly. Furthermore, acyclovir significantly suppressed eosinophil influx into BAL fluid, whereas aminophylline and TBX weakly suppressed the influx.. These results suggest that acyclovir exhibits not only antiviral but also antiasthma activity.

Topics: Acyclovir; Aminophylline; Animals; Anti-Asthmatic Agents; Antiviral Agents; Asthma; Bronchi; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Calcimycin; Eosinophils; Guinea Pigs; Histamine Antagonists; Humans; Male; Middle Aged; Peak Expiratory Flow Rate; Pyridines; Pyrimidinones; Time Factors

To determine whether pemirolast, a new antiallergic drug, inhibits the activation of eosinophils, we investigated the effect of pemirolast on the release of leukotriene C4 (LTC4) and eosinophil cationic protein (ECP) from human eosinophils. Calcium ionophore A23187 caused both LTC4 and ECP release from human eosinophils, whereas PAF and FMLP induced only ECP release from the eosinophils. Pemirolast (10(-6) to 10(-3) M) inhibited A23187-induced LTC4 release from the eosinophils in a dose-dependent fashion with 77% inhibition at 10(-3) M. Pemirolast (10(-5) to 10(-3) M) inhibited A23187-induced ECP release from the eosinophils in a dose-dependent fashion with 42% inhibition at 10(-3) M. Pemirolast (10(-4) and 10(-3) M) also inhibited PAF-induced and FMLP-induced ECP release from the eosinophils. We conclude that pemirolast prevents the activation of human eosinophils to inhibit LTC4 and ECP release. These results suggest that pemirolast might be useful in controlling allergic diseases by inhibiting eosinophil activation.

Topics: Asthma; Blood Proteins; Calcimycin; Eosinophil Granule Proteins; Eosinophils; Humans; In Vitro Techniques; Leukotriene C4; N-Formylmethionine Leucyl-Phenylalanine; Platelet Activating Factor; Pyridines; Pyrimidinones; Ribonucleases; Secretory Rate

Membrane-derived lipid mediators have been considered to play a major role in pathogenesis of bronchial asthma. Recently specific antagonists and synthetase inhibitors of some chemical mediators have been developed and many studies on their anti-asthmatic effects are ongoing. But the importance of and the interactions of each mediator are still unclear. We examined the role of leukotrienes (LTs) and platelet activating factor (PAF) in immediate asthmatic response (IAR) and interactions between these lipid mediators in guinea pig airways in vivo using a specific LTs antagonist AS-35 and a specific PAF antagonist Y-24180. We confirmed the activity of each antagonist, as AS-35 and Y-24180 inhibited bronchoconstriction induced by respective agonist inhalation. AS-35 inhibition IAR but Y-24180 did not, indicating that LTs play a major role in IAR but PAF does not. AS-35 did not influence PAF-induced bronchoconstriction and Y-24180 did not inhibit LTs-induced bronchoconstriction, showing that there is no interaction between LTs and PAF.

Topics: Animals; Asthma; Azepines; Bronchoconstriction; Bronchodilator Agents; Guinea Pigs; Leukotriene Antagonists; Leukotrienes; Male; Platelet Activating Factor; Pyridines; Pyrimidinones; Respiratory Hypersensitivity; Tetrazoles; Triazoles

Effects of a thromboxane A2 receptor antagonist (S-1452) on bronchoconstriction induced by inhaled leukotriene C4 and a leukotriene receptor antagonist (AS-35) on bronchoconstriction caused by inhalation of a thromboxane A2 mimetic (STA2) were studied in anesthetized, artificially ventilated guinea pigs in order to examine the interaction of thromboxane A2 and leukotrienes in airways. 0.01-1.0 mu g/ml of leukotriene C4 and 0.1-1.0 mu g/ml of STA 2 inhaled from ultrasonic nebulizer developed for small animals caused dose-dependent increase of pressure at the airway opening (Pao) which is considered to be an index representing bronchial response. Pretreatment of the animals with inhaled S-1452 (0.01, 0.033 mg/ml) significantly reduced the airway responses produced by 0.01,0.033,0.1,0.33 and 1.0 mu g/ml of leukotriene C4 in a dose dependent manner. While pretreatment with inhaled AS-35 (1mg) did not affect the STA2 dose-response curve. These findings suggest that leukotriene C4 activates thromboxane A2 generation while thromboxane A2 does not influence 5-lipoxygenase pathway in the airways.

Topics: Administration, Inhalation; Animals; Asthma; Bridged Bicyclo Compounds; Bronchoconstriction; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Male; Pyridines; Pyrimidines; Pyrimidinones; Receptors, Immunologic; Receptors, Leukotriene; Receptors, Prostaglandin; Receptors, Thromboxane; SRS-A; Tetrazoles; Thromboxane A2

The effects of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (TBX), a new antiallergic drug, on histamine release from lung fragments, experimental asthma and isolated tracheal muscle were investigated in guinea pigs. TBX (10(-7) to 10(-4) g/ml) dose-dependently inhibited antigen-induced histamine release from lung fragments of guinea pigs passively sensitized with homologous IgE serum. Antigen inhalation-induced experimental asthma in passively sensitized animals was inhibited in a dose-dependent fashion by i.v. (1 to 5 mg/kg) and p.o. (10 to 100 mg/kg) administrations of TBX. In vivo bronchoconstriction by platelet-activating factor (PAF, i.v.) was also inhibited by TBX (0.3 to 10 mg/kg, i.v.). However, high concentrations of TBX (more than 3 x 10(-4) g/ml) were needed to inhibit PAF-induced platelet aggregation in vitro. With regard to the effect on isolated tracheal muscle, TBX itself at concentrations higher than 10(-5) g/ml induced dose-dependent reduction in the resting tonus, which was not affected by pretreatment with propranolol. Neither the leukotriene D4-induced contraction nor the prostaglandin F2 alpha-induced one was specifically antagonized by TBX. The results obtained indicate that TBX is an antiasthmatic agent effective in inhibiting both IgE- and PAF-induced bronchoconstriction, possibly by interfering with mediator release.

Topics: Animals; Asthma; Bronchi; Dinoprost; Guinea Pigs; Histamine Antagonists; Histamine Release; In Vitro Techniques; Lung; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Platelet Activating Factor; Platelet Aggregation; Pyridines; Pyrimidinones; SRS-A; Trachea

Topics: 17-Hydroxycorticosteroids; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Asthma; Child; Child, Preschool; Glycosaminoglycans; Histidine; Humans; Purines; Pyrimidinones; Tryptamines