The effect of pentoxifylline on the 3′,5′-cyclic AMP-system in bovine platelets

Stefanovich, V.; Jarvis, Pam; Grigoleit, H.-G.

doi:10.1016/0020-711x(77)90005-2

Cited by 23 publications

(4 citation statements)

References 15 publications

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“…ylxanthines and dibutyryl cyclic AMP produced the same inhibitory effects, suggesting that the suppressive effect of the drug is mediated through intracellular cyclic AMP and confirming what others had reported earlier, that PTX inhibits phosphodiesterase and elevates cyclic AMP levels in PMNs and other cells (1,4,16). In addition to the direct effect of PTX on TNF-a synthesis, there is evidence, as noted above, that at relatively low concentrations (beginning at 0.1 ,uglml), it may also block the priming effect of preformed TNF-a on PMNs (18), thus minimizing the potential to PMN dysfunction by deactivation (5).…”

Section: Discussionsupporting

confidence: 84%

Efficacy, toxicity, and pharmacokinetics of pentoxifylline and its analogs in experimental Staphylococcus aureus infections

Maderazo

Breaux

Woronick

et al. 1990

Antimicrob Agents Chemother

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Pentoxifylline (PTX), a drug that improves neutrophil function in vitro, has been shown to protect neonatal mice against death from experimental staphylococcal infection in vivo at a dose of 50 mg/kg. Using a total of 774 neonatal mice, the effects of various doses of PTX were examined and compared with the effects of three analogs: HWA-448, HWA-285, and A81-3138. A subcutaneous abscess was induced with 10 Staphylococcus aureus, and drug or saline was given daily subcutaneously from 2 days before to 4 days after infection. Noninfected animals (given saline without S. aureus) had 0% mortality (0 of 66), and infected animals without drug (given saline) had a mortality of 70% (161 of 231). PVX and HWA-448 showed the greatest protection among the drugs tested at 15 mg/kg with mortality rates of 27 and 38%, respectively (Kaplan-Meier method, P = 0.0001 and 0.0004, respectively). HWA-285 was most protective at 25 mg/kg (mortality, 45%; P = 0.0046) and A81-3138 was most protective in animals at 15 mg/kg (mortality, 42%; P = 0.0045). PTX, HWA-448, HWA-285, and A81-3138 at doses of 200, 100, 100, and 50 to 75 mg/kg, respectively, were toxic as shown by worsened weight loss and increased mortality in animals when compared with infected animals without drug.PTX and its analogs decrease mortality from experimental infections at lower doses but are toxic at higher doses. Pharmacokinetic characteristics of the drugs were similar except that HWA-285 produced lower concentrations in serum and A81-3138 showed a dose-dependent kinetics (longer half-life at a higher dose).

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Section: Discussionsupporting

confidence: 84%

Efficacy, toxicity, and pharmacokinetics of pentoxifylline and its analogs in experimental Staphylococcus aureus infections

Maderazo

Breaux

Woronick

et al. 1990

Antimicrob Agents Chemother

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“…Methylxanthines are also known to inhibit phosphodiesterases at high concentrations and this was also found with pentoxifylline (Stefanovich, 1973;Stefanovich et al, 1977;Argel et al, 1978). Inhibition of this enzyme would result in enhanced cyclic AMP, for example after stimulation by catecholamines.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism of action of pentoxifylline is not completely understood. Previous experimental work suggests that pentoxifylline, like other methylxanthines, inhibits phosphodiesterase in several tissues, including the heart (Argel et al, 1980) vascular tissue (Stefanovich, 1973) and platelets (Stefanovich et al, 1977). This may result in enhanced tissue cyclic adenosine-3'5'-monophosphate (cyclic AMP) levels.…”

Section: Introductionmentioning

confidence: 99%

Cardioprotective actions of pentoxifylline in an animal model of acute myocardial ischaemia

Gallenkämper

Rücker

Schrör

1984

British J Pharmacology

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1The action of pentoxifylline on some of the consequences of acute myocardial ischaemia was studied in cats in vivo. 2 Occlusion of the left anterior descending coronary artery (LAD) for 5 h resulted in a significant elevation in the ST-segment of the ECG, a reduction in free platelet count in right atrial blood and a loss of creatine phosphokinase (CK) and cathepsin D activities in homogenates of the severely ischaemic myocardium as compared to non-ischaemic myocardium. 3 Intravenous infusions of pentoxifylline (0.30mgkg-min1 for 1 h and 0.15 mgkg-min-1 for the remainder of the 5 h observation period, starting 0.5 h after LAD occlusion) significantly reduced the loss of enzymes from the ischaemic myocardium, prevented any further increase in the ST-segment and restored the platelet count to its control level.4 There were no significant changes in plasma immunoreactive 6-oxo-prostaglandin Fl, (6-oxoPGF1c,) and thromboxane B2 (TXB2), although a tendency for a reduction in TXB2 levels was observed. 5 Pentoxifylline seems to affect, beneficially, the myocardium in this animal model of acute myocardial ischaemia. The reason for this cardioprotective action remains to be elucidated. It is, however, noteworthy that the overall profile of action of pentoxifylline resembles that of PGI2 administration in this model.

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“…It was previously unclear whether the effects of PTX at therapeutic concentrations are due to modulation of CAMP levels. Pentoxifylline is an inhibitor of cAMP phosphodiesterase, concentrations of about 0.6 mmol/l inhibiting activity by 50% (37). Such high concentrations of pentoxifylline increase the resting level of cAMP in unstimulated human neutrophils and monocytes (22) but at lower concentrations (100-500 pmol/l) significant effects of PTX are more easily seen when adenylate cyclase turnover is increased by stimulation 'with FMLP (18,38) or Fc receptor engagement (39).…”

Section: Discussionmentioning

confidence: 99%

Pentoxifylline at clinically achievable levels inhibits FMLP‐induced neutrophil responses, but not priming, upregulation of cell‐adhesion molecules, or migration induced by GM‐CSF

Roberts

Yong

Khwaja

et al. 1993

European J of Haematology

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Pentoxifylline (PTX) administered after bone‐marrow transplantation reduces procedure‐related organ damage mediated by TNFα. GM‐CSF is also given post‐transplant to stimulate earlier neutrophil recovery. Because PTX has been shown to inhibit neutrophil function, we sought to determine whether it also inhibited the effects of GM‐CSF on neutrophil activity. The study confirmed that PTX at clinically achievable concentration (5–10 μmol/l) attenuated the responses of human neutrophils to chemotactic peptide, whereas it did not inhibit the effect of GM‐CSF on neutrophil function even at high concentrations. In experiments with human neutrophils, neither the direct effects of GM‐CSF such as stimulation of migration and increased expression of CD11b, nor the priming effects of GM‐CSF on the respiratory burst, were inhibited by PTX. In experiments with monkeys, intravenous administration of PTX did not block subsequent GM‐CSF‐induced neutrophil CD11b upregulation or phagocyte margination, even when near millimolar plasma levels of pentoxifylline were obtained. The retention of cytokine‐stimulated activities suggests that PTX will not compromise the response of neutrophils to stimuli from infectious foci.

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The effect of pentoxifylline on the 3′,5′-cyclic AMP-system in bovine platelets

Cited by 23 publications

References 15 publications

Efficacy, toxicity, and pharmacokinetics of pentoxifylline and its analogs in experimental Staphylococcus aureus infections

Efficacy, toxicity, and pharmacokinetics of pentoxifylline and its analogs in experimental Staphylococcus aureus infections

Cardioprotective actions of pentoxifylline in an animal model of acute myocardial ischaemia

Pentoxifylline at clinically achievable levels inhibits FMLP‐induced neutrophil responses, but not priming, upregulation of cell‐adhesion molecules, or migration induced by GM‐CSF

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