Hemodialysis membrane-related neutrophil dysfunctions and pentoxifylline - a pilot study

Hemodialysis treatment is associated with activation of neutrophil granulocytes. Pentoxifylline has been shown to inhibit neutrophil activation in vitro and in vivo. We investigated the effect of pentoxifylline on leukocyte and platelet counts and on plasma levels of extracellularly released neutrophil elastase and lactoferrin during a four-hour hemodialysis treatment. Eight patients received 400 mg of pentoxifylline or placebo orally twice a day over 14 days and an additional dose of 400 mg of pentoxifylline intravenously during hemodialysis. Each subject served as his own control in a randomized, double-blind, cross-over study. Combined oral and intravenous treatment with pentoxifylline prevented neither leukopenia nor neutrophil degranulation during the time interval studied. Elastase plasma levels paralleled the drop in leucocyte counts and thereafter increased similarly in both groups. Lactoferrin plasma levels exhibited less increase in the treated group; however, this effect was not statistically significant. This may be due to the small number of cases studied and to difficulties in reaching effective plasma levels without side effects

In-vitro application of pentoxifylline preserved ultrastructure of spermatozoa after vitrification in asthenozoospermic patients

Abstract PURPOSE: To evaluate the effect of in vitro application of pentoxifylline (PX) on sperm parameters and ultrastructure after vitrification in asthenozoospermic patients. MATERIALS AND METHODS: A total of 30 asthenozoospermic semen samples (aged 25-45 years) were divided into four groups before vitrification, after vitrification, control (without PX) and experimental (with PX). In experimental group, each sample was exposed for 30 min to 3.6mmol/l PX and the control group without any treatment apposing in 370C for 30 min. After incubation, the samples were washed and analyzed again. Vitrification was done according to straw method. Eosin-nigrosin and Papanicolaou staining were applied for assessment of sperm viability and morphology, respectively. The samples without PX and post treatment with PX were assessed by transmission electron microscopy (TEM). RESULTS: A significant decrease in sperm motility (P ≤ .001), morphology (11.47 ± 2.9 versus 6.73 ± 2.01) and viability (73.37 ± 6.26 versus 54.67 ± 6.73) was observed post vitrification, but sperm motility (19.85 ± 4.75 versus 32.07 ± 5.58, P ≤ .001) was increased significantly following application of PX. This drug had no significant (P >.05) detrimental neither negative effect on ultrastructure acrosome, plasma membrane and coiled tail statues of spermatozoa. CONCLUSION: Vitrification had detrimental effects on sperm parameters, but PX reversed detrimental effects on sperm motility. However, PX had no alteration on ultrastructure morphology of human spermatozoa after vitrification

Silence of the limbs: pharmacological symptomatic treatment of intermittent claudication

Several oral "vasoactive" drugs claim to increase walking capacity in patients with intermittent claudication (IC). Naftidrofuryl, cilostazol, buflomedil, and pentoxifylline are the most studied molecules. Although spanning several decades, several studies underlying these claims were not properly designed, underpowered or showed clinically doubtful outcomes. The evidence for these "vasoactive" drugs has always been received with scepticism, creating the need for systematic reviews and meta-analyses. This brief review discusses the benefit-risk assessment of vasoactive drugs, by applying a systematic review to evaluate randomized, placebo-controlled trials. Oral naftidrofuryl and cilostazol have an acceptable safety profile as well as sustained evidence (documented by Cochrane analyses) of increased walking capacity. Subsequently, these drugs entered recommendations for peripheral arterial disease (PAD). In contrast, buflomedil and pentoxifylline have limited and/or doubtful evidence to increase walking capacity. Moreover, there were safety concerns about the narrow therapeutic range of buflomedil. Most other "vasoactive" drugs were either inappropriately or insufficiently tested or showed no significant if not negative effects on IC. "Vasoactive" drugs are no substitutes for lifestyle or exercise therapy but are adjuvant treatment to the well-appreciated triad of cardiovascular prevention (antiplatelet agents, statins and ACE-inhibitors), of which statins in their own right have documented claims to significantly increase walking capacity. "Vasoactive" drugs may have a place in the pharmacological management of symptomatic PAD in addition to the basic cardiovascular pharmacotherapy, when revascularization is not indicated, when exercise therapy is not feasible or when there is still insufficient benefit

Treatment of Schamberg's disease with pentoxifylline - therapeutic trial

Abstract: Thirty patients with Schamberg's disease were started on pentoxifylline (400 mg three times daily) for a period of 9 weeks. Improvement was assessed at 3 weekly intervals by two observers independently and graded as mild (<25%), moderate (25-50%) and marked (>50%). Marked improvement was observed in 15/30 (50%) patients. We conclude that pentoxifylline should be considered as first line therapy in all patients with Schamberg's disease

cAMP-Inhibits Cytoplasmic Phospholipase A(2) and Protects Neurons against Amyloid-beta-Induced Synapse Damage

A key event in Alzheimer’s disease (AD) is the production of amyloid-β (Aβ) peptides and the loss of synapses. In cultured neurons Aβ triggered synapse damage as measured by the loss of synaptic proteins. α-synuclein (αSN), aggregates of which accumulate in Parkinson’s disease, also caused synapse damage. Synapse damage was associated with activation of cytoplasmic phospholipase A2 (cPLA2), an enzyme that regulates synapse function and structure, and the production of prostaglandin (PG) E2. In synaptosomes PGE2 increased concentrations of cyclic adenosine monophosphate (cAMP) which suppressed the activation of cPLA2 demonstrating an inhibitory feedback system. Thus, Aβ/αSN-induced activated cPLA2 produces PGE2 which increases cAMP which in turn suppresses cPLA2 and, hence, its own production. Neurons pre-treated with pentoxifylline and caffeine (broad spectrum phosphodiesterase (PDE) inhibitors) or the PDE4 specific inhibitor rolipram significantly increased the Aβ/αSN-induced increase in cAMP and consequently protected neurons against synapse damage. The addition of cAMP analogues also inhibited cPLA2 and protected neurons against synapse damage. These results suggest that drugs that inhibit Aβ-induced activation of cPLA2 and cross the blood–brain barrier may reduce synapse damage in AD

Regulation of 92-kD gelatinase release in HL-60 leukemia cells

Matrix metalloproteinase 9 (MMP-9), also known as 92-kD type IV collagenase/gelatinase, is believed to play a critical role in tumor invasion and metastasis. Here, we report that MMP-9 was constitutively released from the human promyelocytic cell line HL-60 as determined by zymographic analysis. Tumor necrosis factor-alpha (TNF-alpha) enhanced the enzyme release threefold to fourfold and the protein kinase C (PKC) activator and differentiation inducer 12-O-tetradecanoylphorbol-13- acetate (TPA) eightfold to ninefold. Gelatinase induction by TNF-alpha and TPA was inhibited by actinomycin D or cycloheximide, indicating that de novo protein synthesis was required. Neutralizing monoclonal antibodies to TNF-alpha (anti-TNF-alpha) decreased the basal MMP-9 release of these cells. In addition, these antibodies also significantly interfered with the TPA-induced enzyme release. Agents that inhibit TNF-alpha expression in HL-60 cells, such as pentoxifylline and dexamethasone, completely abrogated both the constitutive and TPA-evoked MMP-9 release. Diethyldithiocarbamate, which is known to stimulate TNF-alpha production in HL-60 cells, exerted a positive effect on MMP-9 release in untreated cells but was inhibitory in TPA-treated HL-60 cells. The PKC inhibitor staurosporine at low concentrations (100 ng/mL) caused a significant augmentation of MMP-9 release in untreated cultures that was blocked by the addition of anti-TNF-alpha. High concentrations (2 mumol/L) of staurosporine completely abolished the extracellular enzyme activity both in untreated and TPA-stimulated cells. These results suggest, that TNF- alpha is required for basal and PKC-mediated MMP-9 release in HL-60 leukemia cells. Thus, MMP-9 secretion may be regulated by TNF-alpha not only in a paracrine but also in an autocrine fashion. This may potentiate the matrix degradative capacity of immature leukemic cells in the processes of bone marrow egress and the evasion of these cells into peripheral tissue

Impending anterior ischemic optic neuropathy with elements of retinal vein occlusion in a patient on interferon for polycythemia vera.

We describe the course and likely pathophysiology of impending anterior ischemic optic neuropathy (AION) and retinal vein occlusion in a 56-year-old man with polycythemia vera managed with interferon alpha for 2 years. Our patient presented with decreased vision, scintillating scotomata, and floaters. Fundus examination findings and results of a fluorescein angiogram led to the diagnosis of impending AION and retinal vein occlusion. Considering that both polycythemia vera and interferon have possible influences on vascular occlusion and optic disc edema, we stopped interferon treatment and immediately attempted to treat the polycythemia vera empirically with pentoxifylline and any interferon-associated inflammation with prednisone. Our patient experienced complete resolution of fundus abnormalities and return of normal vision within 3 weeks, which may be attributed to our successful treatment of both etiologies. Thus, further study is warranted to elucidate the treatment of both polycythemia vera and interferon-induced impending AION

Pharmacokinetics and pharmacodynamics of pentoxifylline and metabolites

Pentoxifylline is a haemorheologic drug with complex pharmacokinetics and pharmacodynamics due to both reversible metabolism and the formation of active metabolites. In humans, pentoxifylline is metabolised to at least seven phase 1 metabolites (M1-M7). The reversible metabolism of pentoxifylline to the enantiomers of M1 has only been partly studied. This thesis investigates the pharmacokinetics of pentoxifylline and metabolites and their contributions to the haemorheological effects. When pentoxifylline is administered either orally or intravenously to healthy humans the plasma concentrations of M5 and S-M1 are higher than the pentoxifylline concentrations, whereas the ones for M4 are lower and R-M1 much lower. In-vitro studies showed that this can be mainly explained by a 15 times faster formation of S-M1 than R-M1 from pentoxifylline. Had the enantiomers been present at equal concentrations the reversible metabolism would have been 4 times faster from S-M1 than from R-M1. Pentoxifylline, R-M1, and M5 increases retinal blood flow after administration of pentoxifylline to healthy humans. In the following potency order R-M1, rac-M1, S-M1, pentoxifylline and M4 significantly inhibit platelet aggregation in a concentration-dependent manner in whole blood from healthy humans. The thesis also includes a phase two, double-blind, placebo-controlled randomised clinical trial investigating pentoxifylline and vitamin E treatment for prevention of radiation-induced side effects in 83 women with breast cancer. The study showed that the combination of pentoxifylline and vitamin E was well tolerated and may be used for prevention of some radiation-induced side effects, e.g. increased arm volume and pain described as stiffness in the skin

Vasodilatory effect of pentoxifylline in isolated equine digital veins

The direct vasodilatory action of pentoxifylline (1-(5-oxohexyl)-3,7-dimethylxanthine) and its signalling pathway was evaluated in equine digital veins. Cumulative concentration-response curves to pentoxifylline (1 nM to 300 μM) were recorded in phenylephrine-precontracted equine digital vein rings under different experimental conditions. Relaxation to pentoxifylline was partially inhibited by endothelium removal, but was unaltered by CGS-15943 (a non-xanthine adenosine receptor antagonist; 3 μM). Nitric oxide synthase (NOS), soluble guanylate cyclase and cyclooxygenase (COX) inhibitors (Nω-nitro-L-arginine methyl ester (100 μM), ODQ (30 μM) and indomethacin (10 μM), respectively) significantly reduced the maximum relaxation induced by pentoxifylline. Moreover, pentoxifylline-induced relaxation was strongly reduced by Rp-8-Br-PET-cyclic guanosine monophosphate-S (a protein kinase G inhibitor; 3 μM), but remained unaffected by H-89 (a protein kinase A inhibitor; 2 μM). Pentoxifylline-induced relaxation was associated with a 3.4-fold increase in tissue cGMP content. To investigate whether pentoxifylline can affect cAMP- and cGMP-mediated relaxations, curves to forskolin, to sodium nitroprusside (SNP) and 8-bromo-cGMP were also recorded in endothelium-denuded equine digital vein rings pretreated with pentoxifylline (10 and 100 μM). Pentoxifylline only potentiated the SNP-mediated relaxation at the highest concentration (100 μM). Thus, pentoxifylline relaxed equine digital veins via endothelium-dependent and endothelium-independent components. The effect was mediated through both the NOS and COX pathways and could also result from inhibition of cGMP specific-phosphodiesterase activity at the highest concentrations used

Dynamics of Micropollutant Adsorption to Polystyrene Surfaces Probed by Angle-Resolved Second Harmonic Scattering

Angle-resolved second harmonic scattering is used to probe the adsorption dynamics of aqueous cationic and anionic dye molecules onto polystyrene surfaces. The adsorptions of malachite green to negatively charged polystyrene and naphthol yellow S to positively charged polystyrene are both highly favorable, with Î"GAds values of -10.9 ± 0.2 and -10.27 ± 0.09 kcal/mol, respectively. A competitive displacement methodology was employed to obtain values for the adsorption free energies of various smaller neutral organic molecules, including the important micropollutant ascorbic acid, caffeine, and pentoxifylline. For charged adsorbers, electrostatic interactions appear to significantly contribute to adsorption behavior. However, electrostatic repulsion does not necessarily deter the adsorption of molecules with large uncharged moieties (e.g., surfactants). In these cases, the mechanism of adsorption is dominated by van der Waals interactions, with the surface charge playing a relatively minor role