The Experts below are selected from a list of 198 Experts worldwide ranked by ideXlab platform
Paul C Marker - One of the best experts on this subject based on the ideXlab platform.
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abstract 1835 phosphodiesterase 4d pde4d selective inhibitors as candidate drugs for prostate cancer
Cancer Research, 2012Co-Authors: Paul C Marker, Kimberly D P HammerAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Our laboratory used an insertional somatic mutagenesis screen in mice to identify novel genes that may drive prostate cancer initiation and progression. Using this screen, we have identified candidate prostate cancer genes including the candidate oncogene phosphodiesterase 4D (PDE4D). Investigation of PDE4D showed that it was over-expressed in human prostate cancer cell lines and in human prostate cancers. Stable knockdown of PDE4D by shRNA reduced the growth and migration of prostate cancer cells in vitro and in vivo. Several small molecule PDE4D-selective inhibitors have been developed, including Cilomilast and NVP-ABE171, and we have used them as potential anti-prostate cancer drugs in vitro and in vivo. The inhibitors were able to reduce the growth of prostate cancer cells in the context of epithelial mono-cultures or co-cultures that modeled stromal-epithelial interactions. Daily oral administration of PDE4D inhibitors for 6 weeks also reduced the growth of several prostate cancer xenograft lines in vivo through a dramatic induction of apoptosis. Interestingly, NVP-ABE171 and Cilomilast also reduced the size of the prostates of treated mice without impacting overall animal health or the sizes of other organs. Under in vitro conditions in which prostate cancer cell growth was inhibited by either NVP-ABE171 or Cilomilast, we also observed changes in the activation of potential downstream molecular targets of PDE4D inhibition including the sonic hedgehog and mitogen-activated protein kinase pathways. We are continuing studies with these inhibitors to further support the use of NVP-ABE171 and Cilomilast as anti-prostate cancer drugs and to understand their mechanism(s) of action in the prostate. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1835. doi:1538-7445.AM2012-1835
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abstract 3046 phosphodiesterase 4d pde4d as a new drug target for prostate cancer
Cancer Research, 2011Co-Authors: Kimberly D P Hammer, Maribella Domenech, David J Beebe, Paul C MarkerAbstract:Our laboratory used an insertional somatic mutagenesis screen in mice to identify novel genes that may drive prostate cancer initiation and progression. Using this screen, we have identified candidate prostate cancer genes including the candidate oncogene phosphodiesterase 4D (PDE4D). Investigation of PDE4D showed that it was over-expressed in human prostate cancer cell lines and in human prostate cancers. Stable knockdown of PDE4D by shRNA reduced the growth and migration of prostate cancer cells in vitro and in vivo. PDE4D has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Several small molecule PDE4D selective inhibitors have been developed and tested in clinical trials for COPD. Although these studies showed that the inhibitors had modest efficacy as a therapy for COPD, they confirmed that the inhibitors were safe for use in humans at doses that inhibited PDE4D in vivo. Based on our previous studies with PDE4D, we postulated that PDE4D small molecule inhibitors would be candidate anti-prostate cancer drugs. Daily oral administration of PDE4D inhibitors, NVP-ABE171 or Cilomilast, for 6 weeks significantly reduced the growth of LNCaP-C4 prostate cancer xenografts in immune-compromised mice. Under in vitro conditions in which prostate cancer cell growth was inhibited by either NVP-ABE171 or Cilomilast, we also observed changes in the activation of potential downstream molecular targets of PDE4D inhibition. Affected pathways included the sonic hedgehog and mitogen-activated protein kinase pathways. We also tested the potential role of the PDE4D pathway in prostate cancer stromal-epithelial interactions by modeling these interactions using novel microchannel co-culture devices. In this context, PDE4D inhibitors reduced the activation of Shh pathway target genes in mesenchymal cells and reduced the proliferation of epithelial cancer cell lines, supporting the potential importance of the PDE4D pathway for prostate cancer stromal-epithelial interactions. We are continuing in vitro and in vivo studies with these candidate drugs to further support the use of NVP-ABE171 and Cilomilast as anti-prostate cancer drugs and to understand their mechanism of action. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3046. doi:10.1158/1538-7445.AM2011-3046
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abstract lb 153 pde4d as a new prostate cancer drug target
Cancer Research, 2010Co-Authors: Kimberly D P Hammer, Paul C MarkerAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC We have been conducting a two-species screen for prostate cancer oncogenes that are suitable for use as new prostate cancer drug targets. The initial screen utilized transposon-based somatic mutagenesis in mice to induce prostate tumors and molecularly tag candidate oncogenes. This approach identified several candidate prostate cancer genes including known oncogenes such as Nras and Braf as well as new candidate oncogenes including Pde4d. A secondary screen used human prostate tissue microarrays (TMAs) to validate the relevance of new candidate oncogenes for understanding human prostate cancer. Automated quantitative analysis of PDE4D protein expression on the human TMAs confirmed its over-expression in human prostate cancer patients. The Pde4d mRNA is alternatively spliced to encode a family of related PDE4D enzymes. These enzymes share a common catalytic domain that gives all of the enzymes cAMP-specific 3′,5′-cyclic phosphodiesterase activity. Protein domains outside the catalytic domain allow for differential protein regulation and sub-cellular localization of different PDE4D isoforms. Several small molecules have been identified that are highly selective inhibitors of PDE4D activity including Cilomilast and NVP-ABE171. In vitro testing of these small molecules has shown that they inhibit the growth of some but not all commonly used prostate cancer cell lines. Growth-inhibition was associated with down-regulation of the MEK-ERK and Shh signaling pathways. Current studies are investigating the molecular mechanisms associated with differential sensitivity/resistance to PDE4D inhibition as well as the potential use of PDE4D inhibitors as anti-prostate cancer drugs in vivo. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-153.
Kimberly D P Hammer - One of the best experts on this subject based on the ideXlab platform.
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abstract 1835 phosphodiesterase 4d pde4d selective inhibitors as candidate drugs for prostate cancer
Cancer Research, 2012Co-Authors: Paul C Marker, Kimberly D P HammerAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Our laboratory used an insertional somatic mutagenesis screen in mice to identify novel genes that may drive prostate cancer initiation and progression. Using this screen, we have identified candidate prostate cancer genes including the candidate oncogene phosphodiesterase 4D (PDE4D). Investigation of PDE4D showed that it was over-expressed in human prostate cancer cell lines and in human prostate cancers. Stable knockdown of PDE4D by shRNA reduced the growth and migration of prostate cancer cells in vitro and in vivo. Several small molecule PDE4D-selective inhibitors have been developed, including Cilomilast and NVP-ABE171, and we have used them as potential anti-prostate cancer drugs in vitro and in vivo. The inhibitors were able to reduce the growth of prostate cancer cells in the context of epithelial mono-cultures or co-cultures that modeled stromal-epithelial interactions. Daily oral administration of PDE4D inhibitors for 6 weeks also reduced the growth of several prostate cancer xenograft lines in vivo through a dramatic induction of apoptosis. Interestingly, NVP-ABE171 and Cilomilast also reduced the size of the prostates of treated mice without impacting overall animal health or the sizes of other organs. Under in vitro conditions in which prostate cancer cell growth was inhibited by either NVP-ABE171 or Cilomilast, we also observed changes in the activation of potential downstream molecular targets of PDE4D inhibition including the sonic hedgehog and mitogen-activated protein kinase pathways. We are continuing studies with these inhibitors to further support the use of NVP-ABE171 and Cilomilast as anti-prostate cancer drugs and to understand their mechanism(s) of action in the prostate. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1835. doi:1538-7445.AM2012-1835
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abstract 3046 phosphodiesterase 4d pde4d as a new drug target for prostate cancer
Cancer Research, 2011Co-Authors: Kimberly D P Hammer, Maribella Domenech, David J Beebe, Paul C MarkerAbstract:Our laboratory used an insertional somatic mutagenesis screen in mice to identify novel genes that may drive prostate cancer initiation and progression. Using this screen, we have identified candidate prostate cancer genes including the candidate oncogene phosphodiesterase 4D (PDE4D). Investigation of PDE4D showed that it was over-expressed in human prostate cancer cell lines and in human prostate cancers. Stable knockdown of PDE4D by shRNA reduced the growth and migration of prostate cancer cells in vitro and in vivo. PDE4D has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Several small molecule PDE4D selective inhibitors have been developed and tested in clinical trials for COPD. Although these studies showed that the inhibitors had modest efficacy as a therapy for COPD, they confirmed that the inhibitors were safe for use in humans at doses that inhibited PDE4D in vivo. Based on our previous studies with PDE4D, we postulated that PDE4D small molecule inhibitors would be candidate anti-prostate cancer drugs. Daily oral administration of PDE4D inhibitors, NVP-ABE171 or Cilomilast, for 6 weeks significantly reduced the growth of LNCaP-C4 prostate cancer xenografts in immune-compromised mice. Under in vitro conditions in which prostate cancer cell growth was inhibited by either NVP-ABE171 or Cilomilast, we also observed changes in the activation of potential downstream molecular targets of PDE4D inhibition. Affected pathways included the sonic hedgehog and mitogen-activated protein kinase pathways. We also tested the potential role of the PDE4D pathway in prostate cancer stromal-epithelial interactions by modeling these interactions using novel microchannel co-culture devices. In this context, PDE4D inhibitors reduced the activation of Shh pathway target genes in mesenchymal cells and reduced the proliferation of epithelial cancer cell lines, supporting the potential importance of the PDE4D pathway for prostate cancer stromal-epithelial interactions. We are continuing in vitro and in vivo studies with these candidate drugs to further support the use of NVP-ABE171 and Cilomilast as anti-prostate cancer drugs and to understand their mechanism of action. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3046. doi:10.1158/1538-7445.AM2011-3046
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abstract lb 153 pde4d as a new prostate cancer drug target
Cancer Research, 2010Co-Authors: Kimberly D P Hammer, Paul C MarkerAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC We have been conducting a two-species screen for prostate cancer oncogenes that are suitable for use as new prostate cancer drug targets. The initial screen utilized transposon-based somatic mutagenesis in mice to induce prostate tumors and molecularly tag candidate oncogenes. This approach identified several candidate prostate cancer genes including known oncogenes such as Nras and Braf as well as new candidate oncogenes including Pde4d. A secondary screen used human prostate tissue microarrays (TMAs) to validate the relevance of new candidate oncogenes for understanding human prostate cancer. Automated quantitative analysis of PDE4D protein expression on the human TMAs confirmed its over-expression in human prostate cancer patients. The Pde4d mRNA is alternatively spliced to encode a family of related PDE4D enzymes. These enzymes share a common catalytic domain that gives all of the enzymes cAMP-specific 3′,5′-cyclic phosphodiesterase activity. Protein domains outside the catalytic domain allow for differential protein regulation and sub-cellular localization of different PDE4D isoforms. Several small molecules have been identified that are highly selective inhibitors of PDE4D activity including Cilomilast and NVP-ABE171. In vitro testing of these small molecules has shown that they inhibit the growth of some but not all commonly used prostate cancer cell lines. Growth-inhibition was associated with down-regulation of the MEK-ERK and Shh signaling pathways. Current studies are investigating the molecular mechanisms associated with differential sensitivity/resistance to PDE4D inhibition as well as the potential use of PDE4D inhibitors as anti-prostate cancer drugs in vivo. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-153.
Manfred Kietzmann - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological studies of bronchial constriction inhibited by parasympatholytics and Cilomilast using equine precision-cut lung slices.
Berliner und Munchener tierarztliche Wochenschrift, 2010Co-Authors: Ann Kristin Barton, Manfred Kietzmann, Frank Niedorf, Achim D. Gruber, Bernhard OhnesorgeAbstract:Equine precision cut lung slices (PCLS) were used to evaluate the ability of several pharmacologic compounds, parasympatholytics atropine, ipratropium, tiotropium and phosphodiesterase (PDE) 4-inhibitor Cilomilast, to inhibit methacholine (MCh) induced bronchial constriction. The study war performed using vital lung samples from 20 horses, harvested immediately after euthanasia and lung examination.Tissue samples from the cranial, caudal and accessory lobe were taken for histological examination. Viability in PCLS of 250 +/- 20 microm was confirmed by observation of cilia movement and bronchial contraction in response to the addition of increasing concentrations of MCh (10(-8) to 10(-4) mol/l). Washing in pure RPMI-medium resulted in bronchial reopening. After incubation (20 minutes in an RPMI-solution containing Cilomilast (10(-5) mol/l), atropine, ipratropium or tiotropium (10(-7) mol/l) each group (randomized, placebo controlled) was treated with MCh again. After reopening the unaffected viability of the PCLS was confirmed by the addition of MCh. EC50 values were calculated from bronchial cross-sections for each contraction. EC50 values significantly increased after atropine, ipratropium and tiotropium addition. No difference was found for Cilomilast and in control slices. Statistical analysis showed a large interindividual, but a small intraindivual variability. No correlation was found between the clinical examination, histological findings and PCLS' responsiveness. We were able to confirm Vietmeier's (2007) values for the responsiveness of equine PCLS to MCh and to proof the effect of several new bronchodilatators using a new technique that allows the assessment of several substances in the same horse.
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effects of cyclosporin a and Cilomilast on activated canine murine and human keratinocytes
Veterinary Dermatology, 2007Co-Authors: Wolfgang Bäumer, Manfred KietzmannAbstract:The calcineurin inhibitor cyclosporin A and the phosphodiesterase 4 inhibitor Cilomilast exhibit potent immunomodulatory properties which make them interesting therapeutics for the treatment of skin disorders like canine and human atopic dermatitis. Cyclosporin A and phosphodiesterase 4 inhibitors have already demonstrated clinical efficacy in the therapy of canine and human atopic dermatitis. Their direct impact on keratinocytes, especially canine keratinocytes, is less obvious. Thus, an investigation was carried out to ascertain whether cyclosporin A and Cilomilast modulate keratinocyte proliferation and secretion of proinflammatory mediators. Cyclosporin A inhibited canine and murine keratinocyte proliferation, whereas Cilomilast had no affect. Cyclosporin A and Cilomilast reduced the lipopolysaccharide-induced prostaglandin E2 synthesis in canine and murine keratinocytes. Both immunomodulators also inhibited the production of the CXC chemokine KC and CCL2 in the murine keratinocyte cell line MSC-P5. The two immunomodulators also significantly reduced the interferon-gamma-induced production of interferon-gamma-inducible protein 10 in human keratinocytes (HaCaT cells). Thus, cyclosporin A and Cilomilast directly modulate keratinocyte functions which might contribute to the anti-inflammatory and immunomodulatory action of these compounds in the treatment of allergic skin diseases.
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Cilomilast tacrolimus and rapamycin modulate dendritic cell function in the elicitation phase of allergic contact dermatitis
British Journal of Dermatology, 2005Co-Authors: Wolfgang Bäumer, Thomas Tschernig, Boris Sülzle, H Weigt, M Hecht, V C De Vries, Manfred KietzmannAbstract:Summary Background Cilomilast and tacrolimus as well as rapamycin are potential drugs for the treatment of allergic skin diseases like atopic dermatitis and allergic contact dermatitis. Objectives To compare the in vitro and in vivo immunomodulatory effects of the phosphodiesterase 4 inhibitor Cilomilast with those of tacrolimus and rapamycin. Methods The in vitro action of Cilomilast, tacrolimus and rapamycin were tested in a mixed leucocyte reaction (MLR). In vivo, the inhibitory action of the immunomodulatory drugs was compared in the toluene-2,4-diisocyanate (TDI)-induced allergic inflammatory response with particular focus on dendritic cell (DC) function. Results Cilomilast, tacrolimus and rapamycin were all able to inhibit DC-mediated T-cell activation in a MLR. But it was demonstrated for Cilomilast that the target cells are T cells rather than DC. In vivo, a combination of systemic and topical administration of each of these three substances significantly inhibited swelling in the murine ear 16 h after TDI challenge. There was also a reduction in the weight of the draining auricular lymph node, in lymphocyte cell count, and in the number of emigrated DC. The density of Langerhans cells in the epidermis was correspondingly higher in mice treated with Cilomilast, tacrolimus and rapamycin than in those treated with vehicle. All three substances were found to inhibit DC migration ex vivo in a skin DC migration assay performed on ear tissue after TDI challenge. Conclusions DC migration into the draining lymph node also takes place in the elicitation phase of allergic contact dermatitis and this migration can be influenced by tacrolimus and rapamycin, and, to a lesser extent, by Cilomilast.
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Cilomilast an orally active phosphodiesterase 4 inhibitor for the treatment of copd
Expert Review of Clinical Immunology, 2005Co-Authors: Wolfgang Baeumer, Istvan Szelenyi, Manfred KietzmannAbstract:Cilomilast is a highly selective, orally active phosphodiesterase (PDE)4 inhibitor currently under evaluation for the treatment of chronic obstructive pulmonary disease (COPD). PDE4 is the predominant cyclic AMP-degrading enzyme in various inflammatory cells such as eosinophils, neutrophils, macrophages, T-cells and monocytes. As a second-generation PDE4 inhibitor, Cilomilast demonstrates a markedly improved side-effect profile over the prototype rolipram. In humans, Cilomilast is rapidly absorbed after oral administration and is almost completely bioavailable with nearly no first-pass hepatic metabolism. Cilomilast has been shown to be well tolerated in both short- and long-term studies in doses of up to 15 mg twice daily. Phase II and III studies demonstrated improvements in lung function and quality of life in patients with COPD. Significant reduction was observed in subepithelial neutrophil, CD68(+) monocyte and CD8(+) lymphocyte densities in bronchial biopsies of COPD patients following administration of Cilomilast for 12 weeks. As there are no pharmacokinetic interactions between Cilomilast and commonly prescribed drugs such as theophylline, salbutamol, erythromycin and corticosteroids, or with smoking, it can be assumed that no dose adjustments will be required in patients with COPD. Cilomilast is thus a promising substance for use in the anti-inflammatory treatment of COPD.
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tarc and rantes but not ctack are induced in two models of allergic contact dermatitis effects of Cilomilast and diflorasone diacetate on t cell attracting chemokines
British Journal of Dermatology, 2004Co-Authors: Wolfgang Bäumer, Thomas Tschernig, Ulrike Seegers, Michael C Braun, Manfred KietzmannAbstract:Summary Background Skin-infiltrating T cells play a predominant role in allergic and inflammatory skin diseases such as atopic dermatitis and allergic contact dermatitis. These T cells are attracted by chemotactic factors, e.g. RANTES (regulation on activation, normal T cell expressed and secreted; CCL5), TARC (thymus and activation regulated chemokine; CCL17) and CTACK (cutaneous T-cell attracting chemokine; CCL27). Objectives To investigate which T-cell-attracting chemokines are involved in allergic contact dermatitis in mice. Methods Allergic contact dermatitis was induced by application of dinitrochlorobenzene (DNCB) or toluene-2,4-diisocyanate (TDI), and chemokine concentrations were determined by enzyme-linked immunosorbent assay. The effects on chemokine concentrations of the highly selective phosphodiesterase 4 inhibitor Cilomilast and the glucocorticoid diflorasone diacetate were studied in mouse ears. Results RANTES and TARC were elevated in both models of allergic contact dermatitis 24 h after challenge, whereas CTACK remained unchanged. The increase in RANTES was diminished in mouse ears pretreated with Cilomilast or diflorasone diacetate. TARC was reduced by diflorasone diacetate in the DNCB model but was highly induced in the TDI model; in contrast, TARC was not influenced by Cilomilast. Conclusions TARC and RANTES, but not CTACK, are involved in these two models of allergic contact dermatitis.
Robert D Murdoch - One of the best experts on this subject based on the ideXlab platform.
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effects of Cilomilast a selective phosphodiesterase 4 inhibitor on esophageal motility and ph and orocecal and colonic transit two single center randomized double blind placebo controlled two part crossover studies in healthy volunteers
Clinical Therapeutics, 2006Co-Authors: Lesley A Houghton, Robert D Murdoch, Dawn M Webber, Wendy Atkinson, P J Whorwell, Julie Morris, Stephen M Cooper, Christine WallsAbstract:BACKGROUND: Phase IIb studies have reported that Cilomilast, a selective phosphodiesterase 4 inhibitor being developed for the treatment of chronic obstructive pulmonary disease, is associated with gastrointestinal (GI) adverse effects (AEs) in a small proportion (approximately 5%) of individuals. OBJECTIVES: The aims of these 2 studies were to investigate the effects of Cilomilast 15 mg BID on: (1) lower esophageal sphincter pressure (LESP) and esophageal body motility and pH (study 1); and (2) orocecal and whole-gut transit times (OCTT and WGTT, respectively) (study 2) in healthy volunteers. METHODS: These 2 randomized, double-blind, placebo-controlled, 2-part crossover studies were conducted at the Neurogastroenterology Unit, Wythenshawe Hospital, Manchester, United Kingdom (study 1) and GlaxoSmithKline, Harlow, United Kingdom (study 2). In study 1, subjects were randomly assigned to receive either Cilomilast (15 mg BID) or matched placebo (control) for 7 days (13 doses; subjects were not given the evening dose on day 7), and in study 2, Cilomilast (15 mg BID) or matched placebo (control) for 9 days (18 doses) in each of 2 treatment periods. After study drug administration, combined esophageal motility and pH were recorded for 2 hours before and 4 hours after the administration of a standardized meal (2400 kJ [573 kcal]). Sequences of 6 consecutive 5-mL water swallows (separated by 20 seconds) were carried out 60 and 90 minutes (fasting) and 150, 180, 210, 240, 300, and 360 minutes (fed) after study drug administration. OCTT was determined from the increase in breath hydrogen after the meal. WGTT was determined from the time taken to excrete at least 16 of 20 ingested radiopaque markers, ingested as 2 capsules, each containing 10 radiopaque markers, with 240 mL of water. AEs were elicited at specified times throughout each session using nonleading questions, spontaneously reported AEs, and diary cards. RESULTS: Study 1 enrolled 20 subjects (11 men, 9 women; age range, 20-52 years). Study 2 enrolled 16 subjects (10 men, 6 women; age range, 19-48 years). No clinically significant differences in the amplitude (mean difference in postprandial-preprandial AUC0-t/t, 6.09 mm Hg; 95% CI, -10.66 to 22.84), duration (difference, -0.08 second; 95% CI, -0.54 to 0.37), or velocity of propagation (difference, 0.90 cm/s; 95% CI, -0.66 to 2.46) of esophageal contractions, LESP (difference, -0.39 mm Hg; 95% CI, -5.23 to 4.45), or preprandial or postprandial percentage time pH<4 (median differences: preprandial, 0.47% [95% CI, -0.45 to 1.27]; postprandial, -0.005% [95% CI, -1.30 to 6.27]) were found with Cilomilast compared with placebo. No significant differences in OCTT (difference, -0.37 hour; 95% CI, -1.59 to 0.84) or WGTT (difference, -2.96 hours; 95% CI, -20.76 to 14.84) were found with Cilomilast compared with controls. In both studies, the most frequently reported AEs with Cilomilast use were nausea (8/18 in study 1 and 3/16 in study 2) and headache (8/18 in study 1 and 6/16 in study 2); however, these were generally of mild to moderate intensity. Overall, GI AEs did not correlate with changes in GI motility. CONCLUSION: The results of these 2 studies suggest that Cilomilast was not associated with significant changes in esophageal motility and pH or GI transit in these healthy volunteers.
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lack of pharmacokinetic interactions between Cilomilast and theophylline or smoking in healthy volunteers
The Journal of Clinical Pharmacology, 2004Co-Authors: Robert D Murdoch, Barry D Zussman, Paul J Schofield, Dawn M WebberAbstract:The pharmacokinetic profile of Cilomilast (Ariflo®), a selective phosphodiesterase 4 (PDE4) inhibitor, was investigated in three separate studies. Two of these studies explored the drug interaction potential of Cilomilast with the nonselective PDE inhibitor, theophylline, and a third study compared the pharmacokinetic profile of Cilomilast in smokers and nonsmokers. Repeated administration of Cilomilast had no effect on the steady-state pharmacokinetics of theophylline in either a pilot dose-ranging or definitive therapeutic study. At therapeutic doses, the point estimate and 90% confidence interval for theophylline AUC 0 - 1 2 and C m a x were completely contained within the range (0.8, 1.25). Similarly, repeated administration of theophylline had little clinically relevant effect on the steady-state pharmacokinetics of Cilomilast when compared to placebo, as only slight average increases in Cilomilast AUC 0 - 1 2 and C m a x (6% and 3%, respectively) were observed. In addition, mean Cilomilast exposure (AUC 0 - ∞ ) was found to be similar in both smokers and nonsmokers (8.47 ′ 2.20 μg.h/mL and 7.70 ′ 2.25 μg.h/mL, respectively). Throughout all three studies, Cilomilast was well tolerated, and concomitant use of these selective and nonselective inhibitois, although unlikely in the clinic, is hypothetically feasible. Taken together, these studies clearly differentiate Cilomilast from theophylline for drug-drug liability issues in a smoker and nonsmoker population, as well as highlight the potential to switch from one drug to another without undue clinical concern.
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does a single dose of the phosphodiesterase 4 inhibitor Cilomilast 15 mg induce bronchodilation in patients with chronic obstructive pulmonary disease
Pulmonary Pharmacology & Therapeutics, 2003Co-Authors: Diana C Grootendorst, John Kelly, Robert D Murdoch, S A Gauw, R Baan, P J Sterk, Klaus F RabeAbstract:Maintenance treatment with PDE(4) inhibitor Cilomilast improves FEV(1) in chronic obstructive pulmonary disease (COPD) patients. We investigated the acute bronchodilating effects of a single dose of Cilomilast with or without concomitant administration of inhaled salbutamol and/or ipratropium bromide in 21 patients with COPD (mean (SD) age 64 (8.1) y, post-salbutamol FEV(1) 47.7 (13.2) %predicted). FEV(1) was measured before and up to 8 hourly intervals after intake of placebo, Cilomilast, or Cilomilast in combination with inhaled salbutamol 400 microg and/or ipratropium bromide 80 microg. Maximum increase in FEV(1) from pre-dose baseline was calculated after each treatment and differences between treatment arms were analyzed by ANOVA. The mean (SEM) maximum increase in FEV(1) was 139.6 (18.5) ml following Cilomilast and 151.5 (18.5) ml following placebo (95% C.I. for mean difference between Cilomilast and placebo: -67.3, 43.6 ml). Furthermore, combined treatment of Cilomilast with salbutamol or ipratropium resulted in a maximum increase in FEV(1) of 280.7 (25.6) and 297.0 (25.9) ml, respectively, while this was 379.0 (24.6) ml following Cilomilast with both salbutamol and ipratropium (p < 0.01). We conclude that a single dose of Cilomilast does not produce acute bronchodilation in patients with COPD who otherwise respond to inhaled bronchodilators. Our results implicate that the change in lung function seen after long-term treatment with Cilomilast is not the result of acute bronchodilation in patients with COPD.
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Cilomilast ariflo does not potentiate the cardiovascular effects of inhaled salbutamol
Pulmonary Pharmacology & Therapeutics, 2002Co-Authors: Robert D Murdoch, John Kelly, H Cowley, R Higgins, Dawn M WebberAbstract:Abstract We investigated the safety and potential pharmacodynamic interactions arising from the co-administration of inhaled β 2 -agonist salbutamol and Cilomilast (Ariflo®), a new oral phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease and asthma. This was a randomised, double-blind, placebo-controlled, multiple-dose, three-period crossover study involving non-smoking volunteers between the ages of 18 and 50 years. Volunteers were randomly assigned to receive Cilomilast plus nebulised salbutamol, Cilomilast plus nebulised placebo or placebo plus nebulised salbutamol. Each volunteer received Cilomilast (10 mg twice daily) or placebo for 5 days. On day 5, the morning dose of Cilomilast or placebo was followed 1 h later with a single dose of nebulised salbutamol (2.5 mg) or placebo. Primary variables were average change from pre- to 1.5 h post-salbutamol or placebo inhalation in blood pressure, pulse rate, 12-lead ECG and total number of heartbeats measured by 4-h Holter ECG. Thirteen volunteers completed the study. There was no evidence of a clinically important pharmacodynamic interaction between Cilomilast and salbutamol in healthy volunteers. Both agents were well tolerated. In conclusion, the pharmacodynamic effects associated with salbutamol inhalation were unaffected by co-administration of Cilomilast.
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warfarin pharmacodynamics unaffected by Cilomilast
Annals of Pharmacotherapy, 2001Co-Authors: John Kelly, Robert D Murdoch, David J Clark, Dawn M Webber, Hermann FuderAbstract:OBJECTIVE:To demonstrate a lack of effect of steady-state concentrations of Cilomilast, a new oral phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease, on warfarin-induced anticoagulation.METHODS:This 28–day, randomized, double-blind, placebo-controlled, parallel-group study involved 36 healthy men. All volunteers received warfarin once daily on days 1 through 24 of the study. After a standard 5–mg loading dose on days 1 and 2, the warfarin dose was titrated between days 3 and 10 to achieve a stable prothrombin time, expressed as international normalized ratio (INR). Volunteers received either Cilomilast 15 mg twice daily or placebo on days 18 through 24. The primary end point was the INR on day 24.RESULTS:On day 24, the mean ± SEM INR in subjects receiving concurrent warfarin and Cilomilast was 1.35 ± 0.05, compared with 1.38 ± 0.07 in those receiving concurrent warfarin and placebo. The point estimate (90% CI) for the difference in day 24 INR values between cilomilas...
Dawn M Webber - One of the best experts on this subject based on the ideXlab platform.
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effects of Cilomilast a selective phosphodiesterase 4 inhibitor on esophageal motility and ph and orocecal and colonic transit two single center randomized double blind placebo controlled two part crossover studies in healthy volunteers
Clinical Therapeutics, 2006Co-Authors: Lesley A Houghton, Robert D Murdoch, Dawn M Webber, Wendy Atkinson, P J Whorwell, Julie Morris, Stephen M Cooper, Christine WallsAbstract:BACKGROUND: Phase IIb studies have reported that Cilomilast, a selective phosphodiesterase 4 inhibitor being developed for the treatment of chronic obstructive pulmonary disease, is associated with gastrointestinal (GI) adverse effects (AEs) in a small proportion (approximately 5%) of individuals. OBJECTIVES: The aims of these 2 studies were to investigate the effects of Cilomilast 15 mg BID on: (1) lower esophageal sphincter pressure (LESP) and esophageal body motility and pH (study 1); and (2) orocecal and whole-gut transit times (OCTT and WGTT, respectively) (study 2) in healthy volunteers. METHODS: These 2 randomized, double-blind, placebo-controlled, 2-part crossover studies were conducted at the Neurogastroenterology Unit, Wythenshawe Hospital, Manchester, United Kingdom (study 1) and GlaxoSmithKline, Harlow, United Kingdom (study 2). In study 1, subjects were randomly assigned to receive either Cilomilast (15 mg BID) or matched placebo (control) for 7 days (13 doses; subjects were not given the evening dose on day 7), and in study 2, Cilomilast (15 mg BID) or matched placebo (control) for 9 days (18 doses) in each of 2 treatment periods. After study drug administration, combined esophageal motility and pH were recorded for 2 hours before and 4 hours after the administration of a standardized meal (2400 kJ [573 kcal]). Sequences of 6 consecutive 5-mL water swallows (separated by 20 seconds) were carried out 60 and 90 minutes (fasting) and 150, 180, 210, 240, 300, and 360 minutes (fed) after study drug administration. OCTT was determined from the increase in breath hydrogen after the meal. WGTT was determined from the time taken to excrete at least 16 of 20 ingested radiopaque markers, ingested as 2 capsules, each containing 10 radiopaque markers, with 240 mL of water. AEs were elicited at specified times throughout each session using nonleading questions, spontaneously reported AEs, and diary cards. RESULTS: Study 1 enrolled 20 subjects (11 men, 9 women; age range, 20-52 years). Study 2 enrolled 16 subjects (10 men, 6 women; age range, 19-48 years). No clinically significant differences in the amplitude (mean difference in postprandial-preprandial AUC0-t/t, 6.09 mm Hg; 95% CI, -10.66 to 22.84), duration (difference, -0.08 second; 95% CI, -0.54 to 0.37), or velocity of propagation (difference, 0.90 cm/s; 95% CI, -0.66 to 2.46) of esophageal contractions, LESP (difference, -0.39 mm Hg; 95% CI, -5.23 to 4.45), or preprandial or postprandial percentage time pH<4 (median differences: preprandial, 0.47% [95% CI, -0.45 to 1.27]; postprandial, -0.005% [95% CI, -1.30 to 6.27]) were found with Cilomilast compared with placebo. No significant differences in OCTT (difference, -0.37 hour; 95% CI, -1.59 to 0.84) or WGTT (difference, -2.96 hours; 95% CI, -20.76 to 14.84) were found with Cilomilast compared with controls. In both studies, the most frequently reported AEs with Cilomilast use were nausea (8/18 in study 1 and 3/16 in study 2) and headache (8/18 in study 1 and 6/16 in study 2); however, these were generally of mild to moderate intensity. Overall, GI AEs did not correlate with changes in GI motility. CONCLUSION: The results of these 2 studies suggest that Cilomilast was not associated with significant changes in esophageal motility and pH or GI transit in these healthy volunteers.
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lack of pharmacokinetic interactions between Cilomilast and theophylline or smoking in healthy volunteers
The Journal of Clinical Pharmacology, 2004Co-Authors: Robert D Murdoch, Barry D Zussman, Paul J Schofield, Dawn M WebberAbstract:The pharmacokinetic profile of Cilomilast (Ariflo®), a selective phosphodiesterase 4 (PDE4) inhibitor, was investigated in three separate studies. Two of these studies explored the drug interaction potential of Cilomilast with the nonselective PDE inhibitor, theophylline, and a third study compared the pharmacokinetic profile of Cilomilast in smokers and nonsmokers. Repeated administration of Cilomilast had no effect on the steady-state pharmacokinetics of theophylline in either a pilot dose-ranging or definitive therapeutic study. At therapeutic doses, the point estimate and 90% confidence interval for theophylline AUC 0 - 1 2 and C m a x were completely contained within the range (0.8, 1.25). Similarly, repeated administration of theophylline had little clinically relevant effect on the steady-state pharmacokinetics of Cilomilast when compared to placebo, as only slight average increases in Cilomilast AUC 0 - 1 2 and C m a x (6% and 3%, respectively) were observed. In addition, mean Cilomilast exposure (AUC 0 - ∞ ) was found to be similar in both smokers and nonsmokers (8.47 ′ 2.20 μg.h/mL and 7.70 ′ 2.25 μg.h/mL, respectively). Throughout all three studies, Cilomilast was well tolerated, and concomitant use of these selective and nonselective inhibitois, although unlikely in the clinic, is hypothetically feasible. Taken together, these studies clearly differentiate Cilomilast from theophylline for drug-drug liability issues in a smoker and nonsmoker population, as well as highlight the potential to switch from one drug to another without undue clinical concern.
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Cilomilast ariflo does not potentiate the cardiovascular effects of inhaled salbutamol
Pulmonary Pharmacology & Therapeutics, 2002Co-Authors: Robert D Murdoch, John Kelly, H Cowley, R Higgins, Dawn M WebberAbstract:Abstract We investigated the safety and potential pharmacodynamic interactions arising from the co-administration of inhaled β 2 -agonist salbutamol and Cilomilast (Ariflo®), a new oral phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease and asthma. This was a randomised, double-blind, placebo-controlled, multiple-dose, three-period crossover study involving non-smoking volunteers between the ages of 18 and 50 years. Volunteers were randomly assigned to receive Cilomilast plus nebulised salbutamol, Cilomilast plus nebulised placebo or placebo plus nebulised salbutamol. Each volunteer received Cilomilast (10 mg twice daily) or placebo for 5 days. On day 5, the morning dose of Cilomilast or placebo was followed 1 h later with a single dose of nebulised salbutamol (2.5 mg) or placebo. Primary variables were average change from pre- to 1.5 h post-salbutamol or placebo inhalation in blood pressure, pulse rate, 12-lead ECG and total number of heartbeats measured by 4-h Holter ECG. Thirteen volunteers completed the study. There was no evidence of a clinically important pharmacodynamic interaction between Cilomilast and salbutamol in healthy volunteers. Both agents were well tolerated. In conclusion, the pharmacodynamic effects associated with salbutamol inhalation were unaffected by co-administration of Cilomilast.
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warfarin pharmacodynamics unaffected by Cilomilast
Annals of Pharmacotherapy, 2001Co-Authors: John Kelly, Robert D Murdoch, David J Clark, Dawn M Webber, Hermann FuderAbstract:OBJECTIVE:To demonstrate a lack of effect of steady-state concentrations of Cilomilast, a new oral phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease, on warfarin-induced anticoagulation.METHODS:This 28–day, randomized, double-blind, placebo-controlled, parallel-group study involved 36 healthy men. All volunteers received warfarin once daily on days 1 through 24 of the study. After a standard 5–mg loading dose on days 1 and 2, the warfarin dose was titrated between days 3 and 10 to achieve a stable prothrombin time, expressed as international normalized ratio (INR). Volunteers received either Cilomilast 15 mg twice daily or placebo on days 18 through 24. The primary end point was the INR on day 24.RESULTS:On day 24, the mean ± SEM INR in subjects receiving concurrent warfarin and Cilomilast was 1.35 ± 0.05, compared with 1.38 ± 0.07 in those receiving concurrent warfarin and placebo. The point estimate (90% CI) for the difference in day 24 INR values between cilomilas...
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an overview of the pharmacokinetics of Cilomilast ariflo a new orally active phosphodiesterase 4 inhibitor in healthy young and elderly volunteers
The Journal of Clinical Pharmacology, 2001Co-Authors: Barry D Zussman, John Kelly, Robert D Murdoch, David J Clark, Dawn M Webber, Lisa J Benincosa, Hugh Cowley, James Upward, Peter Wyld, Andreas PortAbstract:The oral pharmacokinetics of Cilomilast (Ariflo®) were investigated in five separate studies in healthy volunteers. Cilomilast was rapidly absorbed, and pharmacokinetics were dose proportional after single and repeat dosing. The elimination half-life was 7 to 8 hours; accordingly, steady state was reached on the 3rd day of dosing. The degree of accumulation following repeat twice-daily dosing was predictable from the data following a single dose. Although systemic exposure (AUC) was, on average, 21% higher in elderly (65-84 years) compared with young subjects, values for C max and t 1/2 were similar, and no difference in tolerability was noted. Single and repeat doses of Cilomilast up to and including 15 mg (dosed before or taken between meals) were well tolerated. Dosing with food reduced the rate of absorption without affecting total bioavailability. Hence, tolerability was optimal in the fed state; repeat doses up to and including 30 mg twice daily after meals were well tolerated following dose titration.