Effects of pentoxifylline on sputum neutrophil elastase and pulmonary function in patients with cystic fibrosis: Preliminary observations

Aronoff, Stephen C.; Quinn, Francis J; Carpenter, Linda S.; Novick, William J.

doi:10.1016/s0022-3476(05)82022-0

Cited by 18 publications

(7 citation statements)

References 25 publications

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“…Interestingly, in vivo administration of theophylline, aminophylline or pentoxifylline (three activators of CFTR) has proven to be of benefit (as bronchodilators) in the treatment of pulmonary infection of CF patients (Larsen et al , 1980; Isles et al , 1983; Knoppert et al , 1988; Pan et al , 1989). Moreover, pentoxifylline may have efficacy as a therapeutic agent for CF lung disease because of its effects on neutrophils (Aronoff et al , 1994). Our results showing that these agents also activate the CFTR channel is intriguing and requires further investigation as to the role of CFTR in pulmonary infection.…”

Section: Discussionmentioning

confidence: 99%

Structural basis for specificity and potency of xanthine derivatives as activators of the CFTR chloride channel

Chappe¹,

Mettey

Vierfond

et al. 1998

British J Pharmacology

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1 On the basis of their structure, we compared the ability of 35 xanthine derivatives to activate the cystic ®brosis transmembrane conductance regulator (CFTR) chloride channel stably expressed in chinese hamster ovary (CHO) cells using the cell-attached patch clamp and iodide eux techniques. 2 Activation of CFTR channels was obtained with 3-mono, 1,3-di or 1,3,7-tri-substituted alkyl xanthine derivatives (enprofylline, theophylline, aminophylline, IBMX, DPMX and pentoxifylline). By contrast, xanthine derivatives substituted at the C8-or N9-position failed to open CFTR channels. 3 The CFTR chloride channel activity was blocked by glibenclamide (100 mM) but not by DIDS (100 mM). 4 Activation of CFTR by xanthines was not mimicked by the calcium ionophore A23187, adenosine, UTP, ATP or the speci®c phosphodiesterase inhibitors rolipram, Ro 20-1724 and milrinone. In addition, we found no correlation between the eect of xanthines on CFTR and on the cellular cyclic AMP or ATP levels. 5 We then synthesized a series of 3,7-dimethyl-1-alkyl xanthine derivatives; among them, 3,7-dimethyl-1-propyl xanthine and 3,7-dimethyl-1-isobutyl xanthine both activated CFTR channels without increasing the intracellular cyclic AMP level, while the structurally related 3,7-dimethyl-1-(2-propenyl) xanthine and 3,7-dimethyl-1-(oxiranyl methyl) xanthine were inactive. 6 Our ®ndings delineate a novel function for xanthine compounds and identify the molecular features that enable xanthine activation of CFTR. These results may be useful in the development of new molecules for studying the pharmacology of chloride channels.

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Section: Discussionmentioning

confidence: 99%

Structural basis for specificity and potency of xanthine derivatives as activators of the CFTR chloride channel

Chappe¹,

Mettey

Vierfond

et al. 1998

British J Pharmacology

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“…Samples were analysed by ELISA for interleukin-8 (using a commercially available kit, Biotrak, Amersham), and TNF-α and interleukin-10 using capture and detector antibodies from PharMingen (San Diego, California, USA), streptavidin-alkaline phosphatase (Amersham) and developed with p-nitrophenyl phosphate disodium (Sigma). Free elastase was measured by a modification of a previously described method 8. Sputum supernatants were diluted 1:20 with 0.1M Tris, 0.5 mol/l sodium chloride and 0.05 mmol/l EDTA.…”

Section: Methodsmentioning

confidence: 99%

“…Orally active non-steroidal anti-inflammatory drugs such as ibuprofen,6 piroxicam,7 and pentoxifylline8 have been used with variable success. Aerosolised secretory leukoprotease inhibitor9 and α 1 -antitrypsin have also been used to combat the excessive neutrophil elastase activity found in the cystic fibrosis lung 10.…”

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confidence: 99%

Randomised controlled trial of inhaled corticosteroids (fluticasone propionate) in cystic fibrosis

Balfour‐Lynn

Klein²,

Dinwiddie³

1997

Archives of Disease in Childhood

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Background-Controlling lung inflammation may be the key to improving morbidity and mortality in cystic fibrosis. Objective-To assess the eVects of inhaled corticosteroids on lung inflammation in cystic fibrosis. Design-Double blind placebo controlled randomised sequence crossover trial. Fluticasone propionate (400 µg/day) was given as a dry powder inhaler for six weeks with a four week washout period before crossover. Outcome measures-Sputum inflammatory markers (interleukin-8, tumour necrosis factor-(TNF-) and neutrophil elastase-both free and bound to 1 -antiprotease), sputum interleukin-10, lung function, and symptomatology. Subjects-Twenty three children from a regional cystic fibrosis centre were enrolled into the study, with mean age 10.3 years (range 7 to 17 years) and mean baseline forced expiratory volume in one second (FEV 1 ) of 64% (range 21% to 102%) predicted for sex and height. One patient was excluded for non-compliance to the study protocol. Results-No significant benefit was shown for the use of fluticasone propionate in any of the outcomes. For sputum interleukin-8 there was an estimated true treatment median diVerence of 142 pg/ml (95% confidence interval (CI) 8 to 2866 pg/ml) in favour of placebo; while for maximal expiratory flow at 25% (MEF 25% ) remaining forced vital capacity predicted for sex and height there was a 15 percentage points (pp) (95% CI 4 to 26 pp) mean treatment diVerence in favour of placebo. Sputum interleukin-10 was undetected in any samples and unaVected by fluticasone propionate. Neither atopic status, baseline FEV 1 , nor concomitant DNase therapy had any eVect on response to treatment. Conclusions-Lack of benefit from fluticasone propionate was most likely due to failure of the drug to penetrate the viscid mucus lining the airways. It is suggested a large multicentre trial with higher doses given for a longer time by a diVerent delivery system is required to assess eYcacy.

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“…Moreover, several lines of studies have also provided evidence showing potential advantages for the combination of tRA with PTX. The reasons include (1) PTX could block cytokine induction and inhibit inflammatory leukocyte infiltration [38, 39], and thus inhibit the retinoic acid syndrome; (2) PTX given by the oral route has a widely safe therapeutic range [40], and oral administration of tRA is more potent than the parental route [41]; (3) PTX which could inhibit the interaction of leukocytes with endothelial cells [21, 22] may decrease the pulmonary leakage syndrome; (4) PTX, which could inhibit activation of coagulation and fibrinolysis induced by endotoxin [42], may further decrease the possibility of coagulopathies in patients with APL; (5) PTX which could improve postirradiation wound healing [43], decreases bone marrow transplantation- and chemotherapy-induced untoward reactions [44], and fortifies patients with malignancy-associated anorexia and cachexia [45], may promote the well-being of patients with tRA treatment who commonly exhibit dryness of skin, mucositis and headache. Thus, it may be worthwhile to further evaluate the effects of the combination of PTX with tRA simply given via oral route as induction therapy in patients with APL.…”

Section: Discussionmentioning

confidence: 99%

Pentoxifylline Synergizes with All-Trans Retinoic Acid to Induce Differentiation of HL-60 Myelocytic Cells, but Suppresses tRA-Augmented Clonal Growth of Normal CFU-GM

Yang

Chao²,

Shaio

1998

Acta Haematol

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All-trans retinoic acid (tRA) has been shown to promote terminal differentiation of promyelocytic leukemia cells, but frequently induce hyperleukocytosis and pulmonary leakage syndrome. Employing pentoxifylline (PTX), a phosphodiesterase inhibitor which could raise intracellular cAMP and modulate leukocyte activation, we sought to investigate if PTX could enhance tRA-induced promyelocytic leukemic cell differentiation but suppress tRA-augmented growth and activation of human granulocytes. tRA could significantly suppress clonal growth of U937 and HL-60 leukemic cells but enhanced the CFU-GM formation of normal bone marrow cells (22 ± 6 vs. 90 ± 16 CFU/well). PTX significantly augmented tRA suppression of clonal growth of U937 and HL-60 leukemic cells but suppressed tRA-augmented CFU-GM formation of normal bone marrow cells (90 ± 16 vs. 25 ± 9 CFU/well). In addition, PTX enhanced tRA-induced growth inhibition and differentiation of promyelocytic HL-60 leukemic cells, but suppressed respiratory burst activation by the immature granulocytic HL-60 cells and suppressed CD11b adhesion molecule expression by mature granulocytes. PTX similar to dibutyric cAMP promoted HL-60 myelocytic leukemic cell differentiation and growth inhibition, whereas PTX, in contrast to dibutyric cAMP which could augment phorbol myristate acetate (PMA)-elicited respiratory burst activity by immature granulocytes, suppressed the PMA-elicited respiratory burst activity by immature and mature granulocytes. PTX did not raise the intracellular cAMP level of HL-60 cells, but partly suppressed the dibutyric cAMP-elicited elevation of intracellular cAMP level. Results from these studies suggest that PTX might act through different signaling pathways to enhance tRA-induced myelocytic leukemic cell differentiation but prevent from hyperreactive normal granulopoiesis and granulocyte activation.

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Effects of pentoxifylline on sputum neutrophil elastase and pulmonary function in patients with cystic fibrosis: Preliminary observations

Cited by 18 publications

References 25 publications

Structural basis for specificity and potency of xanthine derivatives as activators of the CFTR chloride channel

Structural basis for specificity and potency of xanthine derivatives as activators of the CFTR chloride channel

Randomised controlled trial of inhaled corticosteroids (fluticasone propionate) in cystic fibrosis

Pentoxifylline Synergizes with All-Trans Retinoic Acid to Induce Differentiation of HL-60 Myelocytic Cells, but Suppresses tRA-Augmented Clonal Growth of Normal CFU-GM

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