DOCSLIB.ORG

PR 6 2010.Vp:Corelventura

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
PR 6 2010.Vp:Corelventura Pharmacological Reports Copyright © 2010 2010, 62, 11481058 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences Modulating effects of nonselective and selective phosphodiesterase inhibitors on lymphocyte subsets and humoral immune response in mice Marianna Szczypka, Bo¿ena Obmiñska-Mrukowicz Department of Biochemistry, Pharmacology and Toxicology, Faculty of Veterinary Medicine, Wroc³aw University of Environmental and Life Sciences, Norwida 31, PL 50-375 Wroc³aw, Poland Correspondence: Marianna Szczypka, e-mail: [email protected] Abstract: Phosphodiesterase (PDE) inhibitors can regulate the activity of immune cells by increasing intracellular levels of cyclic nucleotides. The aim of this study was to determine the effects of milrinone, a selective PDE3 inhibitor, sildenafil, a selective PDE5 inhibitor, and aminophylline, a nonselective PDE inhibitor, on lymphocyte subsets and humoral immune response in mice when administered in vivo. Aminophylline (20 mg/kg, im), milrinone (1 mg/kg, im) or sildenafil (1 mg/kg, po) were administered to mice either once or five times at 24 h intervals. Some mice were immunized with a sheep red blood cell (SRBC) suspension administered ip either 2 h after the single dose or 2 h after the second of the five doses. In non-immunized mice treated five times with PDE inhibitors, the subsets of T lymphocytes in the thymus and T and B lymphocytes in the spleen and mesenteric lymph nodes were determined 12, 24 or 72 h after the last dose. The humoral immune response was determined on days 4, 7 and 14 after SRBC injection in SRBC-immunized mice treated with PDE inhibitors. A modulating effect of the drugs on lymphocyte subpopulations was observed. The greatest impact was observed in splenocyte subpopulations, and resulted in decreased percentages of B cells (CD19+) and increased percentages of T cells (CD3+, CD4+, CD8+). No effect or slight influence of the drugs on anti-SRBC hemagglutinins was observed, but the number of plaque-forming splenocytes was increased. The drugs under investigation did not show a significant immunosuppressive effect. Key words: aminophylline, milrinone, sildenafil, PDE inhibitors, lymphocyte subsets, humoral immune response Abbreviations: cAMP – cyclic adenosine monophosphate, cell activity, including the activity of inflammatory CD – cluster of differentiation, cGMP – cyclic guanosine mono- and immune cells. Phosphodiesterase (PDE) catalyzes phosphate, IL – interleukin, im – intramuscular injection, the hydrolysis of cyclic nucleotides and thereby ip – intraperitoneal injection, PBS – phosphate buffered saline downregulates the intracellular levels of these second solution, PDE – phosphodiesterase, PFC – plaque forming sple- messengers. The PDE isozymes are classified into at nocytes, po – per os, by mouth, 2-ME – 2-mercaptoethanol, SRBC – sheep red blood cells least 11 families that vary in molecular structure, sen- sitivity to endogenous and exogenous regulators, in- tracellular location, affinity to cAMP and/or cGMP and sensitivity to selective inhibitors [4, 6]. For in- Introduction stance, PDE4 is highly selective for cAMP, PDE3 fa- vors cAMP but inactivates both cyclic nucleotides, and PDE5 preferentially inactivates cGMP [41]. The levels of intracellular cyclic nucleotides (cAMP In human T lymphocytes, membrane-bound PDE3 and cGMP) play an important role in the regulation of and cytosolic PDE4 are equally active [18, 40]. The 1148 Pharmacological Reports, 2010, 62, 11481058 PDE inhibitors and lymphocyte subsets and humoral response Marianna Szczypka and Bo¿ena Obmiñska-Mrukowicz soluble fraction also contains PDE7 isozyme [18]. animal care (NIH publication No 86–23, revised Marginal activities of PDE1, PDE2 and PDE5 have 1985), and national laws regarding the protection of been detected in human CD4+ and CD8+ lymphocyte animals were observed. The study protocol was ap- homogenates [40]. However, no differences in PDE proved by the Local Ethics Committee in Wroc³aw, isozyme patterns between CD4+ and CD8+ lympho- Poland (No. 16/04). cytes have been observed [40]. Cytosolic PDE4 is a major cyclic-nucleotide-meta- Drugs and treatment bolizing enzyme in human B lymphocytes, though PDE7 activity has also been found in the soluble frac- The PDE inhibitors aminophylline (20 mg/kg, im, tion. Low activity of PDE3 isozyme have been de- Aminophyllinum, Pliva Kraków, Poland), milrinone tected in the particulate fraction. However, activities (1 mg/kg, im, Corotrope, Sanofi-Synthelabo, Paris, of PDE1, PDE2 and PDE5 in B lymphocytes have not France), and sildenafil (1 mg/kg, po, Pfizer, Sand- been detected [17]. wich, UK) were administered either once or five The influence of selective PDE4 inhibitors and times at 24 h intervals. Mice in the control group re- nonselective PDE inhibitors on the activity of im- ceived phosphate buffered saline (PBS) solution (In- mune cells, including lymphocytes, has been studied stitute of Immunology and Experimental Therapy, extensively [8, 13, 21, 24, 26, 28, 35, 38, 42]. As Wroc³aw, Poland) instead of PDE inhibitors. The vol- a major PDE isozyme in immune cells, PDE4 is ume of each dose was 0.1 ml per animal. Each experi- a principal molecular target for drugs that modulate mental group consisted of eight mice. immunological and inflammatory processes by in- Some mice were immunized with 0.2 ml of 10% creasing intracellular cyclic nucleotide levels [6, 9, sheep red blood cell (SRBC) suspension (4 × 108 12, 41]. Many authors have demonstrated beneficial cells/mouse) given ip 2 h after the single dose or 2 h effects of selective PDE4 inhibitors in the treatment after the second of five doses. The sheep blood was of airway diseases and some autoimmune diseases [2, collected, using sterile techniques, into Alsever’s so- 5, 6, 9, 10, 12]. Fewer reports can be found on the im- lution (prepared in our laboratory) containing glucose munotropic effects of selective inhibitors of other iso- (2.05%), sodium citrate (0.8%), sodium chloride zymes, most of which were conducted in vitro. (0.42%) and citric acid (0.055%) (Archem, Wroc³aw, In our previous study, the effects of a single ad- Poland) and was kept at 4°C for at least 3 days. The ministration of aminophylline, a nonselective PDE in- SRBC suspension in PBS was prepared fresh just hibitor (at a dose of 20 mg/kg, im), milrinone, a selec- prior to use. tive PDE3 inhibitor (at a dose of 1 mg/kg, im), or silde- nafil, a selective PDE5 inhibitor (at a dose of 1 mg/kg, Measurements po), on lymphocyte subsets were determined [39]. The aim of the present investigation was to study The following measurements were taken: (i) the total the effects of five administrations of aminophylline, number of lymphocytes in the thymus, spleen and milrinone or sildenafil on lymphocyte subsets and to mesenteric lymph nodes, (ii) the weight ratio of or- assess the effects of one or five doses of these drugs gans calculated according to the following formula: on humoral immune response in mice. weight of organ (g)/body weight of mouse (g) × 100, (iii) the lymphocyte subpopulations in lymphatic or- gans, (iv) the number of plaque forming cells (PFC) in spleen, and (v) anti-SRBC hemagglutinin titers in Materials and Methods the serum. Animals Assay of subpopulations of thymocytes, splenocytes and lymphocytes of lymph nodes The studies were conducted on 8-week-old female Balb/c mice, each weighing 18–22 g. Experimental Mice were anesthetized with halothane (Narcotan, animals were obtained from the Breeding Center of Zentiva, Prague, Czech Republic) 12, 24 or 72 h after Laboratory Animals of the Institute of Occupational the last drug administration. Thymuses, spleens and Medicine, £ódŸ, Poland. The principles of laboratory mesenteric lymph nodes were removed and placed in Pharmacological Reports, 2010, 62, 11481058 1149 Petri dishes containing sterile, ice-cold PBS. The sus- Jerne et al. [22] with some modifications [32]. The pended cells were released from the lymphatic organs number of PFC in SRBC-immunized mice treated by passage through a nylon mesh and then centrifuged once or five times with PDE inhibitors was deter- (3000 × g, 15 min., 4°C) on a layer of Ficoll 400 (Sigma)/ mined on days 4 and 7 after injection of SRBC. Uropolinum 75% (sodium amidotrizoate, Polpharma S.A., Starogard Gdañski, Poland) in a 1:3 ratio at Determination of anti-SRBC antibodies a density of 1.076. After centrifugation, the cells were in the serum collected from the interphase and washed twice with 4°C PBS supplemented with 1% bovine serum albu- Blood samples were taken by retro-orbital bleeding min (BSA, Sigma). After the second wash, the cells 7 from halothane-anesthetized mice. The sera were were resuspended in PBS with 1% BSA at 1 × 10 obtained by centrifugation of the blood (3500 × g, cells/ml. The viability of each cell suspension, as de- 15 min) and then inactivated at 56°C for 30 min. The termined by trypan blue dye exclusion, was 90–95%. total (IgM + IgG) and 2-mercaptoethanol resistant (IgG) Cells in suspension were stained with monoclonal rat serum hemagglutinin titers were defined by the active anti-mouse CD4:FITC/CD8:RPE dual color reagent hemagglutination test, carried out on microplates, as (Serotec, Kidlington, UK) or monoclonal rat anti-mouse described by Adler [1]. Anti-SRBC hemagglutinin CD19:FITC/CD3:RPE dual color reagent (Serotec, titers in SRBC-immunized mice treated once or five Kidlington, UK) according to the manufacturer’s in- times with PDE inhibitors were determined on days 4, structions. Cells were incubated at 4°C for 30 min and 7 and 14 after SRBC injection. then washed three times with ice-cold PBS. Fluores- cence was analyzed using a flow cytometer (FACS Calibur, Becton-Dickinson Biosciences). Lymphocyte Statistical analysis marker distribution was analyzed using CellQuest 3.1f software. The data obtained in the study were analyzed statisti- t CD subsets (CD4-CD8-, CD4+CD8+, CD4+ and CD8+ cally using Student’s -test.
Load more

Recommended publications
  • Download Product Insert (PDF)
    PRODUCT INFORMATION Piclamilast Item No. 29170 CAS Registry No.: 144035-83-6 Formal Name: 3-(cyclopentyloxy)-N-(3,5-dichloro- 4-pyridinyl)-4-methoxy-benzamide O Synonyms: RP 73401, RPR 73401 Cl H MF: C18H18Cl2N2O3 FW: 381.3 N O Purity: ≥98% O Supplied as: A solid N Storage: -20°C Cl Stability: ≥2 years Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures Piclamilast is supplied as a solid. A stock solution may be made by dissolving the piclamilast in the solvent of choice, which should be purged with an inert gas. Piclamilast is soluble in organic solvents such as ethanol and DMSO. The solubility of piclamilast in ethanol is approximately 20 mM and approximately 100 mM in DMSO. Description 1 Piclamilast is a phosphodiesterase 4 (PDE4) inhibitor (IC50 = 0.31 nM). It is selective for PDE4 over PDE1, 2,3 PDE2, PDE3, PDE5, and PDE7A in cell-free assays (IC50s = >100, 40, >100, 14, and >10 μM, respectively). Piclamilast inhibits superoxide production by guinea pig eosinophils and histamine-induced contraction 1,4 in isolated guinea pig trachea (IC50s = 24 and 2 nM, respectively). It inhibits eosinophil, neutrophil, lymphocyte, and TNF-α accumulation in bronchoalveolar lavage fluid (BALF) from ovalbumin-sensitized 5 rats (ED50s = 23.8, 14.1, 19.5, and 14.4 μmol/kg, respectively). Piclamilast also inhibits ovalbumin-induced 2 bronchoconstriction in a guinea pig model of asthma (ED50 = 0.033 mg/kg). References 1. Ashton, M.J., Cook, D.C., Fenton, G., et al. Selective type IV phosphodiesterase inhibitors as antiasthmatic agents.
    [Show full text]
  • [3H]-Piclamilast and [3H]-Rolipram
    JPET Fast Forward. Published on January 24, 2003 as DOI: 10.1124/jpet.102.047407 JPET FastThis articleForward. has not Published been copyedited on and January formatted. 24,The final2003 version as DOI:10.1124/jpet.102.047407 may differ from this version. Inhibitor Binding to Type 4 Phosphodiesterase (PDE4) Assessed Using [3H]-Piclamilast and [3H]-Rolipram Yu Zhao, Han-Ting Zhang, and James M. O’Donnell Department of Pharmacology University of Tennessee Health Science Center Downloaded from Memphis, Tennessee jpet.aspetjournals.org at ASPET Journals on September 27, 2021 1 Copyright 2003 by the American Society for Pharmacology and Experimental Therapeutics. JPET Fast Forward. Published on January 24, 2003 as DOI: 10.1124/jpet.102.047407 This article has not been copyedited and formatted. The final version may differ from this version. Running title: Inhibitor binding to PDE4 Correspondence should be addressed to: James M. O’Donnell, Ph.D. Department of Pharmacology University of Tennessee Health Science Center 874 Union Avenue Downloaded from Memphis, TN 38163 jpet.aspetjournals.org Phone: 901-448-3621 Fax: 901-448-3849 Email: [email protected] at ASPET Journals on September 27, 2021 Number of text page: 31 Number of tables: 3 Number of figures: 7 Number of references: 50 Number of words: Abstract (241); Introduction (716); Discussion (1544) Abbreviations: EHNA, erythro-9-(2-hydroxy-3-nonyl)adenine; HARBS, high-affinity rolipram binding site; LARBS, low-affinity rolipram binding site; IBMX, 3-isobutyl-1- methylxanthine; PDE, phosphodiesterase Section: Neuropharmacology 2 JPET Fast Forward. Published on January 24, 2003 as DOI: 10.1124/jpet.102.047407 This article has not been copyedited and formatted.
    [Show full text]
  • Chapter Introduction
    VU Research Portal Trypanosoma brucei phosphodiesterase B1 as a drug target for Human African Trypanosomiasis Jansen, C.J.W. 2015 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Jansen, C. J. W. (2015). Trypanosoma brucei phosphodiesterase B1 as a drug target for Human African Trypanosomiasis. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 05. Oct. 2021 An introduction into phosphodiesterases and their potential role as drug targets for neglected diseases Chapter 1 4 CHAPTER 1 1.1 Human African Trypanosomiasis Human African Trypanomiasis (HAT), also known as African sleeping sickness, is a deadly infectious disease caused by the kinetoplastid Trypanosoma
    [Show full text]
  • Stems for Nonproprietary Drug Names
    USAN STEM LIST STEM DEFINITION EXAMPLES -abine (see -arabine, -citabine) -ac anti-inflammatory agents (acetic acid derivatives) bromfenac dexpemedolac -acetam (see -racetam) -adol or analgesics (mixed opiate receptor agonists/ tazadolene -adol- antagonists) spiradolene levonantradol -adox antibacterials (quinoline dioxide derivatives) carbadox -afenone antiarrhythmics (propafenone derivatives) alprafenone diprafenonex -afil PDE5 inhibitors tadalafil -aj- antiarrhythmics (ajmaline derivatives) lorajmine -aldrate antacid aluminum salts magaldrate -algron alpha1 - and alpha2 - adrenoreceptor agonists dabuzalgron -alol combined alpha and beta blockers labetalol medroxalol -amidis antimyloidotics tafamidis -amivir (see -vir) -ampa ionotropic non-NMDA glutamate receptors (AMPA and/or KA receptors) subgroup: -ampanel antagonists becampanel -ampator modulators forampator -anib angiogenesis inhibitors pegaptanib cediranib 1 subgroup: -siranib siRNA bevasiranib -andr- androgens nandrolone -anserin serotonin 5-HT2 receptor antagonists altanserin tropanserin adatanserin -antel anthelmintics (undefined group) carbantel subgroup: -quantel 2-deoxoparaherquamide A derivatives derquantel -antrone antineoplastics; anthraquinone derivatives pixantrone -apsel P-selectin antagonists torapsel -arabine antineoplastics (arabinofuranosyl derivatives) fazarabine fludarabine aril-, -aril, -aril- antiviral (arildone derivatives) pleconaril arildone fosarilate -arit antirheumatics (lobenzarit type) lobenzarit clobuzarit -arol anticoagulants (dicumarol type) dicumarol
    [Show full text]
  • Phosphodiesterase (PDE)
    Phosphodiesterase (PDE) Phosphodiesterase (PDE) is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases. The cyclic nucleotide phosphodiesterases comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They regulate the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains. PDEs are therefore important regulators ofsignal transduction mediated by these second messenger molecules. www.MedChemExpress.com 1 Phosphodiesterase (PDE) Inhibitors, Activators & Modulators (+)-Medioresinol Di-O-β-D-glucopyranoside (R)-(-)-Rolipram Cat. No.: HY-N8209 ((R)-Rolipram; (-)-Rolipram) Cat. No.: HY-16900A (+)-Medioresinol Di-O-β-D-glucopyranoside is a (R)-(-)-Rolipram is the R-enantiomer of Rolipram. lignan glucoside with strong inhibitory activity Rolipram is a selective inhibitor of of 3', 5'-cyclic monophosphate (cyclic AMP) phosphodiesterases PDE4 with IC50 of 3 nM, 130 nM phosphodiesterase. and 240 nM for PDE4A, PDE4B, and PDE4D, respectively. Purity: >98% Purity: 99.91% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 1 mg, 5 mg Size: 10 mM × 1 mL, 10 mg, 50 mg (R)-DNMDP (S)-(+)-Rolipram Cat. No.: HY-122751 ((+)-Rolipram; (S)-Rolipram) Cat. No.: HY-B0392 (R)-DNMDP is a potent and selective cancer cell (S)-(+)-Rolipram ((+)-Rolipram) is a cyclic cytotoxic agent. (R)-DNMDP, the R-form of DNMDP, AMP(cAMP)-specific phosphodiesterase (PDE) binds PDE3A directly.
    [Show full text]
  • Inhibition of Phosphodiesterase 4 Modulates Cytokine Induction From
    University of Groningen Inhibition of phosphodiesterase 4 modulates cytokine induction from toll like receptor activated, but not rhinovirus infected, primary human airway smooth muscle Van Ly, David; De Pedro, Monique; James, Peter; Morgan, Lucy; Black, Judith L.; Burgess, Janette K.; Oliver, Brian G. G. Published in: Respiratory Research DOI: 10.1186/1465-9921-14-127 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2013 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Van Ly, D., De Pedro, M., James, P., Morgan, L., Black, J. L., Burgess, J. K., & Oliver, B. G. G. (2013). Inhibition of phosphodiesterase 4 modulates cytokine induction from toll like receptor activated, but not rhinovirus infected, primary human airway smooth muscle. Respiratory Research, 14, [127]. https://doi.org/10.1186/1465-9921-14-127 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
    [Show full text]
  • The Use of Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances
    WHO/PSM/QSM/2006.3 The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances 2006 Programme on International Nonproprietary Names (INN) Quality Assurance and Safety: Medicines Medicines Policy and Standards The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 © World Health Organization 2006 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
    [Show full text]
  • Suplementum 12/1 MAKETA 7/1 2/23/12 12:12 PM Stránka 16
    suplementum 12/1 _MAKETA 7/1 2/23/12 12:12 PM Stránka 16 16 ACTA MEDICA MARTINIANA 2012 Suppl. 1 DOI: 10.2478/v10201-011-0023-7 SELECTIVE INHIBITION OF PHOSPHODIESTERASE 7 (PDE7) BY BRL50481 IN HEALTHY AND OVALBUMIN-SENSITIZED GUINEA PIGS Christensen I.1, Miskovicova H. 1, Porvaznik I.1,JoskovaM.1, Mokra D.2, Mokry J.1 1Department of Pharmacology Jessenius Faculty of Medicine, Comenius University, Martin 2Department of Physiology, Jessenius Faculty of Medicine, Comenius University, Martin, Slovak Republic A b stract Phosphodiesterase (PDE) inhibitors may have significant clinical benefit in respiratory diseases associated with inflammation. The aim was to evaluate effects of selective PDE7 inhibitor (BRL50481) on citric acid induced cough, in vivo and in vitro airway smooth muscle reactivity in both healthy and ovalbumin sensitized guinea pigs, as well as its effectiveness in changes of blood cells count. Tested drugs were administered intraperitoneally to male guinea pigs once daily for 7 days either vehicle 10% DMSO (dimethyl sulfoxide) 3 ml/kg (as control) or BRL50481 1 mg/kg. Double chamber whole body plethysmo- graph was used for evaluation of citric acid (0.6 M) induced cough and specific airway resistance. Organ bath method was used for measurement of tracheal and lung tissue strips contractions evoked by cumulative doses (10- 8 – 10-3 mol/L) of acetylcholine (ACH) and histamine (HIS). In healthy guinea pigs we did not observe significant effect of tested drug BRL50481 on in vitro contractions (sim- ilarly to in vivo conditions). The effect on cough was in healthy animals negligible. In ovalbumin-sensitized ani- mals, more pronounced in vitro relaxing effect of BRL50481 in HIS induced contractions was observed with simi- lar results in vivo and no significant change in number of cough efforts.
    [Show full text]
  • New Therapeutic Options in the Management of COPD – Focus on Roflumilast
    International Journal of COPD Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW New therapeutic options in the management of COPD – focus on roflumilast Sabina Antonela Antoniu Abstract: In chronic obstructive pulmonary disease (COPD) the inflammation occurring in the University of Medicine and Pharmacy, airways and in other lung tissues is complex and is orchestrated by various mediators including the Pulmonary Disease Division, isoenzyme 4 of the phosphodiesterases family (PDE4), which contributes to bronchoconstriction Pulmonary Disease University and inflammation. Various PDE4 inhibitors have been evaluated as potential therapies in asthma Hospital, Iasi, Romania or COPD but among these only roflumilast have been authorized in Europe to be used in patients with severe COPD as an add-on to the bronchodilator therapy. This review discusses the existing preclinical and clinical data supporting the use of roflumilast for this therapeutic indication and tackles some of the pending issues related to PDE4 in general and to roflumilast in particular. Keywords: COPD, roflumilast, PDE4, efficacy, safety Introduction COPD is an inflammatory disease of the airways related mainly to smoking and char- acterized by airflow limitation, which manifests clinically with dsypnea, cough, and sputum production, symptoms that aggravate disease severity and disease exacerbation. Chronic airways inflammation leads to their progressive obstruction, lung paren- chyma damage, and mucus hypersecretion. Subsequently these result in abnormalities in gas exchange at the pulmonary level and respiratory failure. Currently COPD is classified in 4 stages of severity depending on the degree of airways obstruction measured by FEV1 and with FEV1/FVC% ratio (Table 1). In COPD the therapeutic approach is aimed at treating disease exacerbation when this occurs and at slowing disease progression in the stable state.
    [Show full text]
  • Downloaded from Survive Nursing | Survivenursing.Com V20110426
    Generic Stem Stem Definition Examples -abine (see -arabine, -citabine) decitabine -ac Anti-inflammatory agents (acetic acid derivatives) bromfenac; dexpemedolac -acetam See -racetam -actide Synthetic corticotropins seractide -adol or -aldol- Analgesics (mixed opiate receptor agonists/ antagonists) tazadolene; spiradolene; levonantradol -adox Antibacterials (quinoline dioxide derivatives) carbadox -afenone Antiarrhythmics (propafenone derivatives) alprafenone; diprafenone -afil PDE5 inhibitors tadalafil -aj- Antiarrhythmics (ajmaline derivatives) lorajmine -aldrate Antacid aluminum salts magaldrate -algron Alpha1 - and alpha2 - adrenoreceptor agonists dabuzalgron -alol Combined alpha and beta blockers labetalol; medroxalol -amivir (see -vir) -ampa Ionotropic non-NMDA glutamate receptors (AMPA and/or KA receptors) -ampanel Ionotropic non-NMDA glutamate receptors (AMPA and/or KA receptors) ; becampanel antagonists -ampator Ionotropic non-NMDA glutamate receptors (AMPA and/or KA receptors) ; forampator modulators -andr- Androgens nandrolone -anib Angiogenesis inhibitors semaxanib -anserin Serotonin 5-HT2 receptor antagonists altanserin; tropanserin; adatanserin -antel Anthelmintics (undefined group) carbantel -antrone Antineoplastics; anthraquinone derivatives pixantrone -apsel P-selectin antagonists torapsel -arabine Antineoplastics (arabinofuranosyl derivatives) fazarabine; fludarabine aril-, -aril, -aril- Antiviral (arildone derivatives) pleconaril; arildone; fosarilate -arit Antirheumatics (lobenzarit type) lobenzarit; clobuzarit -arol
    [Show full text]
  • Selective Phosphodiesterase 4 Inhibitors
    Journal of Scientific & Indu strial Research Vol. 62, June 2003, pp 537-553 Selective Phosphodiesterase 4 Inhibitors - Emerging Trends in Astluna Therapy (Antiasthmatics-3) Ranju Gupta*, Oeepika Gandhi and Oharam Paul Jindal University In stitute of Pharmaceuti cal Sciences, Panjab Universit y, Chandigarh 160014 Considerable interest has been generated in th e potential utility of isozyme selective inhibitors of phosph odiesterases in the treatment of asthma and other inflali1matory disorders. Heterogeneity in ti ssue distribution as well as their different fun cti onal roles make these enzymes very attractive targets for medicinal chemi sts. To date at least II different fami lies of POE isozymes are known, among which POE 4 plays a major rol e in mod ul ating the activity of virtu ally all cell s involved in the inflammatory process. In hibitors of thi s enzyme family display impressive antiasthmatic ac ti vity by red ucing th e bronchial smooth mu scle tone and consid erable anti-inflammatory activity. The review details th e various classes of POE 4 inhibitors stru cturall y related to rolipram, nitraquazone and xa nthines, which appear to be very attractive models for synthesis of novel selecti ve POE 4 inhibitors potentially useful for the treatment of asthma and chronic obstructive pulmonary di seases. Rationale for the use of POE4 inhibitors in th e treatment of asthma is also discussed. Key words: Phosphodiesterase 4 inhibitors, Asthma therapy, Antiasthmatics, Isozyme, Rol ipram, Nitraquazonc. Xanthincs. Introduction Phosphodiesterase Superfamily There has been growing interest in recent years At least e leven different fami li es of POE tn the utility of selective phosphodiesterase (POE) isozymes are known based on the ir substrate inhibitors as novel targets for drug d iscovery.
    [Show full text]
  • 1 Elevated Intracellular Camp Concentration Mediates Growth
    Elevated intracellular cAMP concentration mediates growth suppression in glioma cells Dewi Safitri1,2, Matthew Harris1, Harriet Potter1, Ho Yan Yeung1, Ian Winfield1, Liliya Kopanitsa3, Fredrik Svensson3,4, Taufiq Rahman1, Matthew T Harper1, David Bailey3, Graham Ladds1, *. 1 Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, United Kingdom 2 Pharmacology and Clinical Pharmacy Research Group, School of Pharmacy, Bandung Institute of Technology, Bandung 40132, Indonesia 3 IOTA Pharmaceuticals Ltd, Cambridge University Biomedical Innovation Hub, Clifford Allbutt Building, Hills Road, Cambridge CB2 0AH, United Kingdom 4 Computational Medicinal Chemistry, Alzheimer’s Research UK UCL Drug Discovery Institute, The Cruciform Building, Gower Street, London, WC1E 6BT *Corresponding author: Dr Graham Ladds, Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD Tel; +44 (0) 1223 334020. Email: [email protected]. ABSTRACT Supressed levels of intracellular cAMP have been associated with malignancy. Thus, elevating cAMP through activation of adenylyl cyclase (AC) or by inhibition of phosphodiesterase (PDE) may be therapeutically beneficial. Here, we demonstrate that elevated cAMP levels suppress growth in C6 cells (a model of glioma) through treatment with forskolin, an AC activator, or a range of small molecule PDE inhibitors 1 with differing selectivity profiles. Forskolin suppressed cell growth in a PKA-dependent manner by inducing a G2/M phase cell cycle arrest. In contrast, trequinsin (a non- selective PDE2/3/7 inhibitor), not only inhibited cell growth via PKA, but also stimulated (independent of PKA) caspase-3/-7 and induced an aneuploidy phenotype. Interestingly, a cocktail of individual PDE 2,3,7 inhibitors suppressed cell growth in a manner analogous to forskolin but not trequinsin.
    [Show full text]