Pentoxifylline for endometriosis.

BACKGROUND: Endometriosis is a chronic, recurring condition that occurs during the reproductive years. It is characterized by endometrial tissue developing outside the uterine cavity. This endometrial tissue development is dependent on oestrogen produced primarily by the ovaries and, therefore, traditional management has focused on ovarian suppression. In this review we considered the role of modulation of the immune system as an alternative approach. This is an update of a Cochrane Review previously published in 2009 (Lu 2009). OBJECTIVES: To assess the effects of pentoxifylline, which has anti-inflammatory effects, in subfertile, premenopausal women for the management of endometriosis. SEARCH METHODS: For the first publication of this review we searched the following databases (from inception to December 2008) for trials: Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, CINAHL, and PsycINFO. In addition, all reference lists of included trials were searched and experts in the field were contacted in an attempt to locate trials. This search was rerun to 23 November 2011, for this update. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing pentoxifylline with placebo or no treatment, medical treatment, or surgery in subfertile, premenopausal women were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed trial risk of bias, and extracted data using data extraction forms. We contacted study authors for additional information and data. The domains assessed for risk of bias were sequence generation, allocation concealment, blinding, incomplete outcome data, and selective outcome reporting. Peto odds ratios (OR) were used for reporting dichotomous data with 95% confidence intervals (CI), whilst mean differences (MD) were expressed for continuous data. Statistical heterogeneity was assessed using the I(2) statistic. MAIN RESULTS: Four trials involving 334 participants were included. One RCT [n=34] showed pentoxifylline had no significant effect on reduction in pain (MD -1.60, 95% CI -3.32 to 0.12). There was no evidence of an increase in clinical pregnancy events in the pentoxifylline group compared with placebo (three RCTs [n=67] OR 1.54, 95% CI 0.89 to 266). One RCT studied recurrence of endometriosis [n=88] (OR 0.88,95% CI 0.27 to 2.84). No trials reported the effects of pentoxifylline on the odds of live birth rate per woman, improvement of endometriosis-related symptoms, or adverse events. AUTHORS' CONCLUSIONS: This review has been updated in 2011. The results of the original review published in 2009 remain unchanged. There is still not enough evidence to support the use of pentoxifylline in the management of premenopausal women with endometriosis in terms of subfertility and relief of pain outcomes.

Effects of pentoxifylline during Schistosoma mansoni infection in Swiss mice: an analysis of worm burden, fecundity and liver histopathology.

The short-term effects of pentoxifylline (PTX) on granulomatous lesions during Schistosoma mansoni infection in Swiss mice were evaluated. Drug administration was initiated 42 and 140 days post-infection (DPI) for the acute and chronic infection groups, respectively. Treatment was carried out daily with 200 mg/kg (subcutaneous route) of the drug for five consecutive days. Recovery of parasites and tissues was performed at 49 DPI and 147 DPI, respectively. Liver histological analysis showed a decrease in the inflammatory reaction and fibrous content of the granulomas studied, and a significant reduction (P < 0.001) in their mean diameter was observed in the groups of rodents treated with PTX in acute and chronic infection, when compared to their respective control groups. However, no alteration in the number of S. mansoni recovered from the portal system was observed, and egg-laying kinetics was not notably modified by PTX treatment, and the immature stage distribution of S. mansoni eggs showed minor intrinsic variations with no statistical differences in the parameter second-stage/female/g among untreated mice and treated mice in acute and chronic infections, respectively, when evaluated by intestinal oograms. Data obtained indicate probable immunomodulatory effects of PTX in murine schistosomiasis both in acute and chronic infection.

Effect of interferon-alpha, ribavirin, pentoxifylline, and interleukin-18 antibody on hepatitis C sera-stimulated hepatic stellate cell proliferation.

Chronic hepatitis C virus (HCV) infection is a major cause of liver fibrosis ultimately leading to cirrhosis. Hepatic stellate cell (HSC) proliferation is crucial in fibrosis development. Current antiviral treatment for HCV involves interferon-alpha (IFN-alpha) and Ribavirin combination therapy. IL-18, a novel cytokine of the IL-1 family of cytokines, is involved in inflammation and may be important in HCV-related inflammation. We hypothesize that block of one of the crucial events will block fibrosis due to HCV. The effect of HCV patient sera with and without IFN-alpha, ribavirin, and IL-18 antibody on HSC proliferation was assessed by [(3)H]-thymidine incorporation assays. Western analysis was used to assess the effect of pentoxifylline (PTX) on c-Jun immediate early gene phosphorylation (p-c-Jun formation). We demonstrate that HCV patient sera-stimulated HSC proliferation. Ribavirin with or without IFN-alpha significantly decreased HCV sera-stimulated HSC proliferation by 50%. Western analysis revealed that HCV serum increased p-c-Jun levels, which were decreased with Ribavirin and PTX. ELISA results showed an elevation of IL-18 levels in HCV sera when compared to normal sera. IL-18 did not stimulate HSC proliferation. However, IL-18 antibody significantly decreased patient sera-stimulated HSC proliferation. In conclusion, Ribavirin decreased HSC proliferation and may act by decreasing p-c-Jun levels in HSCs. IL-18 alone did not stimulate HSC proliferation but IL-18 antibody decreased stimulation, suggesting that IL-18 may work in conjunction with some other factor to increase HSC proliferation.

Immunomodulation, part I: pentoxifylline.

PTXF appears to be a promising adjunct to antibiotic therapy in neonatal sepsis. No adverse effects were noted in either study reported in the literature. However, there is a need for large randomized clinical trials to confirm or refute the role of PTXF in the treatment of sepsis in neonates. Clinically important comorbidities such as chronic lung disease, periventicular leukomalacia, duration of assisted ventilation, and NEC should be evaluated as a part of these studies. Comparison of PTXF with immunomodulatory agents such as colony-stimulating factors and intravenous immunoglobulins is suggested. Part II of this five-part series on immunomodulation will explore the use of colony-stimulating factors in neonates. Other topics will include the amino acid glutamine, intravenous immunoglobulins, and probiotics.

Extrinsic allergic alveolitis: inhibitory effects of pentoxifylline on cytokine production by alveolar macrophages.

BACKGROUND: Pentoxifylline is a well-established drug with hemorheologic properties. Various evidence suggests an additional therapeutic potential in regard to inflammation and immunomodulation. Extrinsic allergic alveolitis (EAA) is a granulomatous disease that is driven by T-cell and alveolar macrophage (AM)-derived cytokines. OBJECTIVE: To investigate the effects of pentoxifylline on the production of tumor necrosis factor (TNF) alpha, interleukin (IL) 1beta, IL-6, IL-8, IL-10, and the soluble TNF receptors (sTNFR1 and sTNFR2) from AMs in EAA compared with dexamethasone. METHODS: The AMs from 9 patients with EAA were cultured for 24 hours with RPMI medium alone or lipopolysaccharide (LPS) (100 ng/mL) and with pentoxifylline at concentrations of 0.01, 0.1, and 1 mmol/L or 0.1-mmol/L dexamethasone. Cytokines in the culture supernatants were analyzed by enzyme-linked immunosorbent assay. RESULTS: Pentoxifylline induced a dose-dependent suppression of spontaneous TNF-alpha and IL-10 release from AMs in EAA. The spontaneous production of other cytokines was unaffected by pentoxifylline at all tested concentrations. Dexamethasone inhibited significantly only the spontaneous release of TNF-alpha. Pentoxifylline and dexamethasone also inhibited the LPS-stimulated production of all cytokines except IL-1beta and sTNFR1. CONCLUSION: Our results may be the basis for clinical trials to evaluate the role of pentoxifylline as an immunotherapeutic agent in the treatment of EAA.

Can polyclonal intravenous immunoglobulin limit cytokine mediated cerebral damage and chronic lung disease in preterm infants?

Recent evidence suggests that inflammatory cytokines may play an important role in cerebral and pulmonary injury, especially in preterm infants. Immunomodulatory agents may help to limit such injury by reducing inflammation. Immunoglobulin has multiple anti-inflammatory properties and can modulate the inflammatory cytokine response. New evidence is required to test the hypotheses that prophylaxis or treatment with intravenous immunoglobulin may limit such inflammatory damage.

Pentoxifylline functions as an adjuvant in vivo to enhance T cell immune responses by inhibiting activation-induced death.

Modalities for inducing long-lasting immune responses are essential components of vaccine design. Most currently available immunological adjuvants empirically used for this purpose cause some inflammation, limiting clinical acceptability. We show that pentoxifylline (PF), a phosphodiesterase (PDE) inhibitor in common clinical use, enhances long-term persistence of T cell responses, including protective responses to a bacterial immunogen, Salmonella typhimurium, via a cAMP-dependent protein kinase A-mediated effect on T cells if given to mice for a brief period during immunization. PF inhibits activation-mediated loss of superantigen-reactive CD4 as well as CD8 T cells in vivo without significantly affecting their activation, and inhibits activation-induced death and caspase induction in stimulated CD4 as well as CD8 T cells in vitro without preventing the induction of activation markers. Consistent with this ability to prevent activation-induced death in not only CD4 but also CD8 T cells, PF also enhances the persistence of CD8 T cell responses in vivo. Thus, specific inhibition of activation-induced T cell apoptosis transiently during immune priming is likely to enhance the persistence of CD4 and CD8 T cell responses to vaccination, and pharmacological modulators of the cAMP pathway already in clinical use can be used for this purpose as immunological adjuvants.

Perinatal immunomodulation.

The fetus and the neonate are particularly vulnerable to injury caused directly by immunologic mechanisms or inflicted by infectious agents that take advantage of their relatively immature and inexperienced immune system. With increasing survival of high-risk neonates in the surfactant era, prevention/treatment of sepsis and chronic lung disease (CLD) has emerged as an area of priority in neonatal research. Considering the role of inflammatory mediators in the pathogenesis of sepsis and CLD, the clinical application of immunomodulator therapy to neonatology is perhaps more important at present than ever. Advances in molecular biology and immunology have led to development of newer immune modulator therapies that are directed towards specific cells or cytokines rather than resulting in a general suppression of the immune response. Failure of promising, newer immunomodulator therapies in sepsis trials in adults has, however, clearly documented the difficulties in diagnosing/correcting the imbalance between pro- and anti-inflammatory responses. As in the case of sepsis, development of a single magic bullet for prevention/management of a multi-factorial illness like CLD may be difficult, as prevention of prematurity - the single most important high-risk factor for CLD - is an unachievable goal at present. As new frontiers are being explored, older, well-established therapies like antenatal anti-D immunoglobulin prophylaxis continue to emphasize the tremendous potential of immunomodulator therapy in neonatology/perinatology. The current immunomodulators/immunotherapeutic agents with established/potential clinical applications in the perinatal period are reviewed.

Pentoxifylline downregulares nitric oxide and tumor necrosis factor-a induced by mycobacterial lipoarabinomannan in a macrophage cell line

Pentoxifylline (PTX), a phosphodiesterase inhibitor, is known to downregulate tumor necrosis factor-alpha (TNF-alpha) secretion induced by lipopolysacchride (LPS) and gamma interferon (IFN-gamma). We have had limited success in treating leprosy reactions, including erythema nodosum leprosum (ENL), in which TNF-alpha has been identified as a major proinflammatory cytokine. PTX inhibited production of NO (IC50 approximately equal to 1.0 mg/ml) and TNF-alpha (IC50 approximately equal to 0.05 mg/ml) in a dose-dependent fashion. As little as 0.5 mg/ml of PTX decreased NO production and 0.01 mg/ml of PTX inhibited TNF-alpha production. Western blot analyses demonstrated that iNOS was suppressed by PTX. Northern blot analyses showed significant reduction of TNF-alpha mRNA. We conclude that PTX is an effective inhibitor of lipoarabinomannan (LAM)-induced TNF-alpha production at both the product and transcriptional levels in our macrophage cell line. PTX also showed moderate inhibition of NO at the product level as well as translation of iNOS.

Pentoxifylline alters class-specific immunoglobulin synthesis in resuscitated burn injury.

Pentoxifylline (PTXF) is a hemorheologic agent that can attenuate microvascular alterations induced by injury, resulting in improved microcirculatory flow. Burn injury-induced immunologic suppression may be caused by alterations in microvascular flow. We studied the effects of PTXF on humoral immunity in resuscitated burn injury. Male AKR mice (n = 80) were randomized to four groups: SHAM, BURN, PTXF-BURN, and NS-BURN (saline burn). Animals were resuscitated with Ringer's lactate and morphine sulfate and put to death at days 1 and 4 after injury. PTXF-BURN animals received PTXF (50 mg/kg intraperitoneally) at the time of resuscitation. Splenic lymphocytes (1 x 10(6) cells/well) were cultured with lipopolysaccharide (LPS) (2.5 and 10 micrograms/ml)). LPS-stimulated in vitro class-specific immunoglobulin (Ig) production was determined by enzyme-linked immunosorbent assay from splenic cell culture supernatants. Burn injury induced a reduction in immunoglobulin (Ig) M synthesis on postburn day 4. PTXF treatment was associated with an increase in IgG production, but a greater depression in IgM synthesis than burn injury alone. PTXF administration during resuscitation in burn injury does not ameliorate the burn-induced depression in IgM synthesis and results in significant potential adverse modulation of humoral immune function.

Differential regulation of IFN-gamma, IL-10 and inducible nitric oxide synthase in human T cells by cyclic AMP-dependent signal transduction pathway.

Expression of cytokines by T lymphocytes is a highly balanced process, involving stimulatory and inhibitory intracellular signalling pathways. In the present work, we attempted to clarify the role of cAMP on interferon-gamma (IFN-gamma), interleukin (IL)-10, IL-4 and IL-13 expression as well as on the inducible nitric oxide synthase (iNOS) expression. Treatment of phytohaemagglutinin (PHA)/phorbol 12-myristate 13-acetate (PMA)-activated Jurkat cells with either dibutyryl-cyclic adenosine monophosphate (cAMP) or pentoxifylline induced a strong inhibition of IFN-gamma mRNA expression as measured by reverse transcription (RT)-polymerase chain reaction (PCR), without affecting IL-10 expression. Both cholera toxin and prostaglandin E2 (PGE2) induced a strong inhibition of IFN-gamma mRNA expression, whereas IL-10 mRNA expression was significantly enhanced. This differential regulation of IFN-gamma and IL-10 expression was related to intracellular cAMP concentration. IL-13 and IL-4 mRNA expressions were not inhibited. We developed a new method based on immunofluorescence for intracellular cytokine detection followed by optical and computerized image processing, and our results showed that IFN-gamma protein was strongly inhibited when cells were treated with PGE2 or dibutyryl (db)-cAMP, whereas IL-10 protein was enhanced. This suggests that cAMP exerts its action at both the transcriptional and protein levels. iNOS mRNA expression was markedly elevated in the presence of PGE2. The generation of nitric oxide using sodium nitroprusside (SNP) induced a dramatic decrease of IFN-gamma, while IL-10 was enhanced; and conversely the inhibition of iNOS activity using 1-NG-monomethyl arginine (1-NMMA) induced a clear inhibition of IL-10 and IL-4, while IFN-gamma was enhanced. These results provide evidence that the protein kinase A (PKA) activation pathway plays a prominent role in the balance between the type 1 and type 2 cytokine profile in PHA/PMA-activated Jurkat cells. Data also suggest that iNOS expression is under the control of PKA activation, and that NO seems to be able to assume the polarization of activated T cells to the type 2 profile.

Pentoxifylline exerts synergistic immunomodulatory effects in combination with dexamethasone or cyclosporin A.

The methylxanthine derivative pentoxifylline (PTX) is an immunomodulatory agent with incompletely characterized effects on cytokine production. To analyse these effects and to delineate new combination strategies in immunotherapy, we have investigated immunomodulatory properties of PTX in combination with dexamethasone (DEX) or cyclosporin A (CsA). Stimulated human peripheral blood mononuclear cells were treated with clinically relevant concentrations of PTX (12.5-100 micrograms/ml), DEX (0.01-10 microM) or CsA (12.5-50 ng/ml), alone or in combination. With increasing doses of PTX the maximum supernatant titres of tumour necrosis factor (TNF)-alpha, interleukin (IL)-2 and interferon (IFN)-gamma decreased concomitantly, and all cultures co-treated with DEX showed synergism. Release of IL-6 was not consistently altered under PTX treatment. Similarly, PTX and CsA synergistically inhibited the release of IL-2, IFN-gamma and, to a lesser degree, TNF-alpha. Although PTX alone did not significantly reduce lymphoproliferation, both combinations of drugs synergistically inhibited this process. Furthermore, to demonstrate that the key mechanism of PTX-induced effects is an increase in intracellular cyclic adenosine 3':5'-monophosphate (cAMP) levels, identical experiments were performed using dibutyryl-cAMP instead of PTX. In cultures treated with PTX and DEX, expression of different cell receptors was analysed. Expression of IL-2 receptor (IL-2R) was reduced in cultures treated with PTX, and combination with DEX led to further reduction. Expression of intercellular adhesion molecule (ICAM)-1 and of leucocyte function antigen (LFA)-1 alpha was also synergistically reduced, though to a lesser degree. HLA-DR expression remained unchanged. In conclusion, we demonstrate that clinically relevant levels of PTX exert profound immunomodulatory effects in vitro, and that the combined treatment with DEX or CsA has synergistic effects.

Pentoxifylline.

Pentoxifylline (oxpentifylline) is a methylxanthine derivative with potent hemorrheologic properties. In the United States it is marketed for the treatment of intermittent claudication. Human and animal studies have shown that pentoxifylline therapy results in a variety of physiological changes at the cellular level, which may be important in treating a diverse group of human afflictions. Immune modulation includes increased leukocyte deformability and chemotaxis, decreased endothelial leukocyte adhesion, decreased neutrophil degranulation and release of superoxides, decreased production of monocyte-derived tumor necrosis factor, decreased leukocyte responsiveness to interleukin 1 and tumor necrosis factor, inhibition of T and B lymphocyte activation, and decreased natural killer cell activity. Hypercoagulable states improve through decreased platelet aggregation and adhesion, increased plasminogen activator, increased plasmin, increased antithrombin III, decreased fibrinogen, decreased alpha 2-antiplasmin, decreased alpha 1-antitrypsin, and decreased alpha 2-macroglobulin. Wound healing and connective tissue disorders may respond to an increase in fibroblast collagenases and decreased collagen, fibronectin, and glycosaminoglycan production. Fibroblast responsiveness to tumor necrosis factor is also diminished. Potential medical uses of pentoxifylline are reviewed.

Pentoxifylline suppresses interleukin-2-mediated activation of immature human natural killer cells by inhibiting endogenous tumor necrosis factor-alpha secretion.

We recently reported that immature human peripheral blood-derived natural killer (NK) cells, the free NK subset, can be activated by interleukin-2 (IL-2) to become killer cells and to undergo proliferation. Activation by IL-2 is dependent on endogenous secretion of tumor necrosis factor-alpha (TNF-alpha) by the free cells. Because pentoxifylline (PTX) inhibits TNF-alpha synthesis and secretion in monocytes, we hypothesized that PTX may also inhibit TNF-alpha secretion by NK cells and thus would inhibit IL-2-mediated activation of free cells. The free NK cells were separated from purified NK cells by flow cytometry and cell sorting of non-target binding cells. IL-2-mediated secretion of TNF-alpha by the free cells was inhibited by PTX. In the presence of PTX, IL-2-mediated activation of free cells into cytotoxic function, proliferation, and recruitment of binder and killer cells was markedly inhibited. Also, PTX inhibited IL-2-triggered upregulation of the expression of CD69, CD25, ICAM-1, and p75TNF-R on the cell surface. These findings demonstrate that PTX has a marked suppression on IL-2-mediated activation of immature free NK cells and that the suppression is due, in large part, to PTX-mediated inhibition of endogenous TNF-alpha secretion. The implication of these findings in the clinical use of PTX for therapy is discussed.