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Background Sulfasalazine and pentoxifylline are co-prescribed together to treat psoriasis and pemphigus vulgaris. Sulfasalazine is an anti-inflammatory, immunosuppressant, and antibiotic drug, while pentoxifylline is a vasodilator and immunosuppressant. The spectra of the two drugs and plasma suffer from severe overlap. Objective This work aims to simultaneously determine sulfasalazine and pentoxifylline in their binary mixture and spiked human plasma by the assessment of their UV spectral data. Methods Two model updated chemometric methods were established using principal component regression and partial least-squares regression models. The two models were validated in accordance with the U.S. Food and Drug Administration guidelines for bioanalysis and were applied for the determination of both drugs in synthetic mixtures or spiked human plasma. Results Accuracy and precision were within the accepted limits. In addition, three different assessment methods were used to evaluate the environmental greenness of the proposed models. Conclusion The two updated models are simple, rapid, sensitive, and precise, and could be easily applied in QC laboratories for determination of sulfasalazine and pentoxifylline, without any preliminary separation steps or interference from plasma matrix. Highlights Two updated chemometric models called principlal component regression and partial least-squares regression were established for determination of sulfasalazine and pentoxifylline in spiked human plasma using UV spectrophotometric data. [ABSTRACT FROM AUTHOR]

Background: Alopecia areata is a nonscarring skin disease affecting the scalp or other body parts. The etiology of AA is still controversial and various pathogenic causes are under investigation. Several treatment modalities are used in managing AA. Objective: to evaluate the efficacy and safety of (PTX) injection in treatment of localized AA compared to intralesional cortico-steroids TRA on 30 patients with multiple patches of AA. Patients and Methods: The current study was a prospective intra-patient comparative controlled clinical trial. Patients were recruited form outpatient clinic of Dermatology, Ain Shams University Hospital in the period from November 2019 to May 2020. 30 Egyptian patients (11 males &19 females) with at least three patches were enrolled to the study. The diagnosis of AA patients enrolled in the study based on clinical signs. Results: To sum up, both PTX and ILCS has good results in treatment of AA, as each of them has its own advantages. Corticosteroids are rapidly acting while PTX effects are delayed but increased progressively throughout consecutive sessions. So using corticosteroids in combination with PTX can augment each other and give better results. Conclusion: Treatment of AA with intralesional PTX exerted significant increase in hair density, total hair count, terminal hair count and percentage of terminal hair which is evident after completion of the sessions. Treatment with ILCS exerted significant increase hair density, total hair count, terminal hair count and percentage of terminal hair after treatment. Comparison of both treatment modalities revealed slight better response with PTX compared to ILCS. In conclusion, the current study revealed that Intralesional combined administration of PTX and TRA can be beneficial for patients suffering from AA. Steroid showed a rapid response that could be maintained by adding PTX. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease is one of the most frequent complications in patients with diabetes and constitutes a major cause of end-stage kidney disease. The prevalence of diabetic kidney disease continues to increase as a result of the growing epidemic of diabetes and obesity. Therefore, there is mounting urgency to design and optimize novel strategies and drugs that delay the progression of this pathology and contain this trend. The new approaches should go beyond the current therapy focussed on the control of traditional risk factors such as hyperglycaemia and hypertension. In this scenario, drug repurposing constitutes an economic and feasible approach based on the discovery of useful activities for old drugs. Pentoxifylline is a nonselective phosphodiesterase inhibitor currently indicated for peripheral artery disease. Clinical trials and meta-analyses have shown renoprotection secondary to anti-inflammatory and antifibrotic effects in diabetic patients treated with this old known drug, which makes pentoxifylline a candidate for repurposing in diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Background and Aims The efficacy of current biologics may be limited by targeting only one pathway. Pentoxifylline [PTX] interferes with tumour necrosis factor [TNF] gene expression. We performed a randomised, placebo-controlled pilot study to determine if PTX plus vedolizumab [VDZ] in patients with Crohn's disease [CD] is safe and improves response compared with VDZ monotherapy. Methods Thirty adult patients with active CD were randomised to VDZ/PTX or VDZ/placebo and followed for 24 weeks. Endoscopic activity and inflammatory cytokines were measured at baseline and Week 24. Descriptive statistics were used to determine estimates of effect. Results Demographics were similar but baseline disease activity was higher in the VDZ/PTX group. There was no difference in clinical remission at Week 14 (60.0% vs 66.67%, odds ratio [OR] 0.76, 95% confidence interval [CI] 0.16, 3.51) or steroid-free clinical remission at Week 24 in patients receiving VDZ/PTX. Improved clinical response was noted in the VDZ/PTX group at Weeks 6, 14, and 24 [Week 6: 20% vs 6.67%, Week 14: 26.67% vs 6.67%, Week 24: 40% vs 20%]. The rate of endoscopic remission was similar between the groups [40% vs 33.33%], with a greater mean decrease in Simple Endoscopic Score-CD [SES-CD] and C-reactive protein [CRP] with VDZ/PTX [SES-CD -3.17 vs -0.15, CRP -5.56 vs 0.46]. An increase in serum TNF-α concentration was observed with VDZ/placebo group; PTX mitigated this effect. No serious adverse events occurred. Conclusions VDZ/PTX did not provide benefit over VDZ monotherapy in clinical or endoscopic remission but appeared to improve clinical response and was safe. These data should inform a fully powered study. [ABSTRACT FROM AUTHOR]

Background Severe alcohol-associated hepatitis (SAH) patients with infections have a high short-term mortality rate. Gut microbiota dysbiosis plays an important role in the pathogenesis of SAH. Preliminary studies have demonstrated long-term benefits with healthy donor fecal microbiota transplantation (FMT). Data on FMT compared with pentoxifylline for SAH and relevant gut microbial changes are lacking in literature. Methods From January 2019 to February 2021, retrospective analysis of a single hospital's records revealed 47 SAH patients undergoing FMT (100 mL/day via nasoduodenal tube for 7 days) and 25 matched patients receiving pentoxifylline (400 mg/8 h for 28 days). The primary end point was a 6-month survival rate. Secondary end points included incidence of ascites, hepatic encephalopathy, infections, acute kidney injury, and gut microbiota changes between post-therapy groups. Biomarker discovery and network analysis were also performed to identify significant taxa of gut microbiota in post-treatment groups in retrospectively stored stool samples. Results All were males. The 6-month survival rate was higher in the patients undergoing FMT than in patients receiving pentoxifylline (83.0% vs 56.0%, P  =   0.012). At the end of 6-month follow-up, the incidences of clinically significant ascites (56.0% vs 25.5%, P  =   0.011), hepatic encephalopathy (40.0% vs 10.6%, P  =   0.003), and critical infections (52.0% vs 14.9%, P  <   0.001) in patients administered pentoxifylline were significantly higher than those in patients treated with FMT. At 3 months, biomarker analysis revealed a significant abundance of Bifidobacterium and Eggerthella in the FMT group and the pentoxifylline group, respectively. At 6 months, Bifidobacterium in the FMT group and pathogenic Aerococcaceae in the pentoxifylline group were notable. Network analysis showed beneficial taxa (Bifidobacterium) as a central influencer in those undergoing FMT at 6 months. Conclusions Healthy donor FMT improved survival rate and reduced liver-related complications compared with pentoxifylline. These clinical benefits were associated with favorable modulation of intestinal bacterial communities. Difficult-to-treat SAH patients may be safely bridged to transplantation using FMT. Controlled trials evaluating long-term outcomes are an unmet need. [ABSTRACT FROM AUTHOR]

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the Paracoccidioides genus. Most of the patients with chronic form present sequelae, like pulmonary fibrosis, with no effective treatment, leading to impaired lung functions. In the present study, we aimed to investigate the antifibrotic activity of three compounds: pentoxifylline (PTX), azithromycin (AZT), and thalidomide (Thal) in a murine model of pulmonary PCM treated with itraconazole (ITC) or cotrimoxazole (CMX). BALB/c mice were inoculated with P. brasiliensis (Pb) by the intratracheal route and after 8 weeks, they were submitted to one of the following six treatments: PTX/ITC, PTX/CMX, AZT/ITC, AZT/CMX, Thal/ITC, and Thal/CMX. After 8 weeks of treatment, the lungs were collected for determination of fungal burden, production of OH-proline, deposition of reticulin fibers, and pulmonary concentrations of cytokines and growth factors. Pb-infected mice treated with PTX/ITC presented a reduction in the pulmonary concentrations of OH-proline, associated with lower concentrations of interleukin (IL)-6, IL-17, and transforming growth factor (TGF)-β1 and higher concentrations of IL-10 compared to the controls. The Pb-infected mice treated with AZT/CMX exhibited decreased pulmonary concentrations of OH-proline associated with lower levels of TGF-β1, and higher levels of IL-10 compared controls. The mice treated with ITC/Thal and CMX/Thal showed intense weight loss, increased deposition of reticulin fibers, high pulmonary concentrations of CCL3, IFN-γ and VEGF, and decreased concentrations of IL-6, IL-1β, IL-17, and TGF-β1. In conclusion, our findings reinforce the antifibrotic role of PTX only when associated with ITC, and AZT only when associated with CMX, but Thal did not show any action upon addition. [ABSTRACT FROM AUTHOR]

Chronic non-communicable diseases have become a pandemic public problem in the 21st century, causing enormous burden on the economy, health and quality of life of societies. The role of a chronic inflammatory state in the pathogenesis of chronic disease has been more comprehensively recognized by recent findings. The new paradigm 'metaflammation' focuses on metabolism-induced (high fat or fructose-based diet or excessive calorie intake) chronic inflammation. There is a close correlation between the increased incidence of chronic kidney disease (CKD) and chronic heart failure with both increased inflammatory marker levels and western-type diet. In this review we describe the concept of metaflammation, its role in the development of CKD and chronic heart disease, the molecular and signalling pathways involved and the therapeutic consequences. [ABSTRACT FROM AUTHOR]

Surrounding the zone of coagulation is the zone of stasis, which is characterized as a mix of viable and nonviable cells, capillary vasoconstriction, and ischemia. Saving the zone of stasis is a major subject of the burn wound studies. If pathological changes in the zone of stasis can be minimized, conversion of burn wounds may be prevented. The aim of this study was to investigate the effects of pentoxifylline (PTX) on the zone of stasis in burns and burn wound healing. Twenty Sprague-Dawley rats were used in this study. Comb model was used to create zone of stasis in burns. Treatment group received a total of 200 mg/kg/d of PTX in two equal doses intraperitoneally whereas isotonic saline solution was given intraperitoneally to the control group. This treatment was continued until postburn day 17. Tissue samples were taken from the burn wounds on postburn days 3, 7, and 17. Fibroblastic and vascular density, inflammatory cells, re-epithelialization rates were assessed in histopathological study. Furthermore, macroscopic healing of burn areas on the right side were compared between the groups by taking pictures on postburn day 17. PTX treatment decreased inflammation of the burn wound in the early postburn period. Comparing the necrotic area between the groups, PTX apparently had lower rate of necrosis. PTX treatment increased re-epithelialization of burns wounds. Our study concluded that systemic treatment of burns by PTX enhances burn wound healing and helps salvaging the damaged but live cells in the zone of stasis by increasing the rate of epithelization, decreasing the necrotic area and preventing the deepening of the burn wound. [ABSTRACT FROM AUTHOR]

Aim: Several drugs have been used for treating non-alcoholic fatty liver disease (NAFLD). The present study is a network meta-analysis of such drugs.Design, Setting and Patients: Randomised clinical trials comparing drug interventions in patients with NAFLD were analysed. OR and weighted mean difference (95 % CI) were the effect estimates for categorical and numerical outcomes, respectively. Random-effects model was used to generate pooled estimates. Surface under the cumulative ranking curve was used to rank the treatments.Main Outcome Measures: Proportion of responders was the primary outcome measure and non-alcoholic steatohepatitis scores, liver enzymes, lipid profile, body mass index, homeostatic model assessment of insulin resistance, intrahepatic fat and adverse events were the key secondary outcomes.Results: 116 studies were included in the systematic review and 106 in the meta-analysis. Elafibranor, gemfibrozil, metadoxine, obeticholic acid, pentoxifylline, pioglitazone, probiotics, telmisartan, vildagliptin and vitamin E significantly increased the response rate than standard of care. Various other drugs were observed to modify the secondary outcomes favourably. Probiotics was found with a better response in children; and elafibranor, obeticholic acid, pentoxifylline and pioglitazone in patients with type 2 diabetes mellitus. The quality of evidence observed was either low or very low.Conclusion: In patients with NAFLD, several drugs have been shown to have variable therapeutic benefit. However, the estimates and the inferences should be considered with extreme caution as it might change with the advent of future head-to-head clinical trials. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Can we identify compound(s) with reported phosphodiesterase inhibitor (PDEI) activity that could be added to human spermatozoa in vitro to enhance their motility without compromising other sperm functions? SUMMARY ANSWER We have identified several compounds that produce robust and effective stimulation of sperm motility and, importantly, have a positive response on patient samples. WHAT IS KNOWN ALREADY For >20 years, the use of non-selective PDEIs, such as pentoxifylline, has been known to influence the motility of human spermatozoa; however, conflicting results have been obtained. It is now clear that human sperm express several different phosphodiesterases and these are compartmentalized at different regions of the cells. By using type-specific PDEIs, differential modulation of sperm motility may be achieved without adversely affecting other functions such as the acrosome reaction (AR). STUDY DESIGN, SIZE, DURATION This was a basic medical research study examining sperm samples from normozoospermic donors and subfertile patients attending the Assisted Conception Unit (ACU), Ninewells Hospital Dundee for diagnostic semen analysis, IVF and ICSI. Phase 1 screened 43 commercially available compounds with reported PDEI activity to identify lead compounds that stimulate sperm motility. Samples were exposed (20 min) to three concentrations (1, 10 and 100 µM) of compound, and selected candidates (n = 6) progressed to Phase 2, which provided a more comprehensive assessment using a battery of in vitro sperm function tests. PARTICIPANTS/MATERIALS, SETTING, METHODS All healthy donors and subfertile patients were recruited at the Medical Research Institute, University of Dundee and ACU, Ninewells Hospital Dundee (ethical approval 08/S1402/6). In Phase 1, poor motility cells recovered from the 40% interface of the discontinuous density gradient were used as surrogates for patient samples. Pooled samples from three to four different donors were utilized in order to reduce variability and increase the number of cells available for simultaneous examination of multiple compounds. During Phase 2 testing, semen samples from 23 patients attending for either routine diagnostic andrology assessment or IVF/ICSI were prepared and exposed to selected compounds. Additionally, 48 aliquots of prepared samples, surplus to clinical use, were examined from IVF (n = 32) and ICSI (n = 16) patients to further determine the effects of selected compounds under clinical conditions of treatment. Effects of compounds on sperm motility were assessed by computer-assisted sperm analysis. A modified Kremer test using methyl cellulose was used to assess sperm functional ability to penetrate into viscous media. Sperm acrosome integrity and induction of apoptosis were assessed using the acrosomal content marker PSA-FITC and annexin V kit, respectively. MAIN RESULTS AND THE ROLE OF CHANCE In Phase 1, six compounds were found to have a strong effect on poor motility samples with a magnitude of response of ≥60% increase in percentage total motility. Under capacitating and non-capacitating conditions, these compounds significantly (P ≤ 0.05) increased the percentage of total and progressive motility. Furthermore, these compounds enhanced penetration into a cervical mucus substitute (P ≤ 0.05). Finally, the AR was not significantly induced and these compounds did not significantly increase the externalization of phosphatidylserine (P = 0.6, respectively). In general, the six compounds maintained the stimulation of motility over long periods of time (180 min) and their effects were still observed after their removal. In examinations of clinical samples, there was a general observation of a more significant stimulation of sperm motility in samples with lower ... [ABSTRACT FROM AUTHOR]

By using a no-choice feeding bioassay, delayed toxicity and concentration-dependent mortality of two chitinolytic enzyme inhibitors, pentoxifylline and psammaplin A, were evaluated by determining LT50, LT90, and LT99 (lethal time) against the economically important eastern subterranean termite, Reticulitermes flavipes (Kollar). Pentoxifylline- and psammaplin A-incorporated diets (filter paper) were assayed at 0.01, 0.02, 0.04, 0.08, and 0.21% and 0.0375, 0.075, 0.15, and 0.3% active ingredient (wt:wt), respectively. Acetone-only treated filter paper served as diet for the control treatments. Termite workers were allowed to feed on diet until 100% test population mortality occurred (80-95 d). Both chitinase inhibitors were shown to be toxic to R. flavipes. Concentrationdependent toxicity occurred within the pentoxifylline treatments over the range of 0.01-0.08%, with 0.08% treatments producing an LT50 of 32.2 d. However, mortality in response to psammaplin A treatments lacked concentration-dependent toxicity. Treatment with 0.3% psammaplin A produced an LT50 of 21.3 d. Mortality in response to lower psammaplin A treatments displayed no concentration-dependent trends. This study provides the first report on delayed toxicity of chitinolytic enzyme inhibitors against eastern subterranean termites (order Isoptera) and toxicological data on pentoxifylline and psammaplin A over a range of concentrations. [ABSTRACT FROM AUTHOR]

Background: A systematic review and network meta-analysis was undertaken to consider the evidence for the efficacy and tolerability of placebo, cilostazol, naftidrofuryl oxalate and pentoxifylline in patients with intermittent claudication due to peripheral arterial disease (PAD). Methods: MEDLINE, Embase, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Conference Proceedings, BIOSIS, National Research Register and MetaRegister databases were searched. Eligible studies were randomized controlled trials (RCTs) and published systematic reviews of patients with intermittent claudication due to PAD and whose symptoms persisted despite a period of conservative management. Study selection was conducted by one reviewer with involvement from a clinician. Data were extracted by one reviewer with no blinding to authors or journal, and checked by a second reviewer. Outcome measures were maximum walking distance (MWD) and pain-free walking distance (PFWD). Results: The review identified 1876 citations; 26 RCTs met the inclusion criteria for the systematic review. Eleven trials provided data relevant for the meta-analysis. Naftidrofuryl oxalate was ranked first for both MWD and PFWD (probability of 0·947 and 0·987, respectively, of being the best treatment) followed by cilostazol and pentoxifylline. For naftidrofuryl oxalate, cilostazol and pentoxifylline, MWD increased by 60 (95 per cent credible interval 20 to 114) per cent, 25 (11 to 40) per cent and 11 (−1 to 24) per cent respectively relative to placebo, and PFWD increased by 49, 13 and 9 per cent. Conclusion: Naftidrofuryl oxalate and cilostazol are both effective treatments for claudication; naftidrofuryl oxalate is likely to be the most effective, with minimal serious adverse events. Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aim. The aim of this study was to compare the effect of pentoxifylline versus placebo on serum concentrations of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and C-reactive protein (CRP) of hemodialysis (HD) patients. Methods. This is a randomized double-blind, controlled clinical trial. HD patients without infection or drugs with anti-inflammatory effect were randomly allocated to a study (n = 18, pentoxifylline 400 mg/day) or control (n = 18, placebo) group; all patients had arteriovenous fistula. Besides clinical and laboratory monthly assessments, serum TNF-α and IL-6 (ELISA) and CRP (nephelometry) were measured at 0, 2 and 4 months. Results. All the inflammation markers significantly (P < 0.05) decreased in the pentoxifylline group: TNF-α [baseline 0.4 (0–2) versus final 0 (0–0) pg/mL], IL-6 [baseline 9.4 (5–14) versus final 2.9 (2–5) pg/mL] and CRP [baseline 7.1 (3–20) versus final 2.6 (1–8) mg/L], whereas no significant changes were observed in the placebo group: TNF-α [baseline 0 (0–0) versus final 1.2 (0–4) pg/mL], IL-6 [baseline 8.0 (5–11) versus final 8.7 (4–11) pg/mL] and CRP [baseline 4.5 (2–9) versus final 3.8 (3–23) mg/L]. Conclusions. Pentoxifylline significantly decreased serum concentrations of TNF-α, IL-6 and CRP compared to placebo. Pentoxifylline could be a promising and useful strategy to reduce the systemic inflammation frequently observed in patients on HD. [ABSTRACT FROM PUBLISHER]

ABSTRACT Introduction. There is no current consensus as to the most effective nonsurgical therapy for Peyronie's disease (PD). Aim. This study aims to assess the benefit of penile traction therapy (PTT) when added to intralesional verapamil injections (IVIs) combined with oral L-arginine 1 g b.i.d. and pentoxifylline 400 mg t.i.d. in men with PD. Methods. Seventy-four men with PD completed 12 IVIs. Patients electing to add PTT were advised to wear the device for 2-8 hours daily and no longer than 2 hours per session. Subjective responses were measured using patient questionnaires. Stretched penile length (SPL) and erect penile curvature (EPC) using penile duplex ultrasound were measured. Response to therapy was defined as at least a 10-degree reduction in EPC. Main Outcome Measures. Change in SPL (cm) and change in EPC (degrees). Results. Thirty-five patients in group I vs. 39 patients in the PTT group II completed the protocol. Fifty-four percent of men in group II responded to therapy vs. 46% in group I ( P = 0.75). Responders in group II had a mean EPC improvement of 26.9 degrees vs. 20.9 degrees in group I ( P = 0.22). Mean PTT use was 3.3 hours per day, and men with >3 hours per day use gained 0.6 cm in SPL vs. 0.07 cm using less than or equal to 3 hours per day ( P = 0.09), while men in group I lost 0.74 cm of SPL on average. Multivariate analysis revealed that duration of PTT use significantly predicts length gain (0.38 cm gain for every additional hour per day of PTT use, P = 0.007). Conclusions. There was a trend toward measured curvature improvement and a significant gain in SPL in men using the combination therapy protocol. Length improvement is related to duration of use of the traction device. Abern MR, Larsen S, and Levine LA. Combination of penile traction, intralesional verapamil, and oral therapies for Peyronie's disease. J Sex Med 2012;9:288-295. [ABSTRACT FROM AUTHOR]

Introduction. Transforming growth factor-β1 (TGF-β1) has been implicated in the pathogenesis of Peyronie's disease (PD) and also plays a role in collagen and elastin metabolism. Pentoxifylline (PTX) antagonizes the effects of TGF-β1 and has been utilized in our clinic for the management of PD. Aim. We studied the effects of TGF-β1 and PTX on collagen metabolism and elastogenesis in tunica albuginea-derived fibroblasts (TADFs). Methods. TADFs from men with and without PD were cultured and treated with TGF-β1 and PTX as monotherapy at differing concentrations and time points. Combination treatment (TGF-β1 followed by PTX and vice versa) was also investigated. Main Outcome Measures. Cell proliferation assay, enzyme-linked immunosorbent assay, and immunohistochemistry were utilized to assess the impact of TGF-β1 and PTX on TADF with respect to elastin and collagen I metabolism. Results. PTX inhibited fibroblast proliferation at doses of 100 µM. TGF-β1 stimulated elastogenesis and collagen I fiber deposition in TADF in a dose- and time-dependent fashion. Pretreatment with PTX dramatically attenuated TGF-β1-mediated elastogenesis and collagen fiber deposition in TADF from men with and without PD. Interestingly, production of collagen I was higher in untreated Peyronie's tunica (PT) cells relative to normal tunica (NT) cells; furthermore, PTX attenuated collagen production to levels similar to untreated control TADF in PT cells but not in NT cells, suggesting important intrinsic differences between PT and NT cells. Conclusion. Both elastin and collagen are upregulated by TGF-β1 in TADF. This likely contributes to the PD phenotype. Pretreatment with PTX attenuates both collagen fiber deposition and elastogenesis in TADF exposed to TGF-β1; these effects suggest a useful role for PTX in the management of PD. Shindel AW, Lin G, Ning H, Banie L, Huang Y-C, Liu G, Lin C-S, and Lue TF. Pentoxifylline attenuates TGF-β1 stimulated collagen deposition and elastogenesis in human tunica albuginea-derived fibroblasts Part 1: Impact on extracellular matrix. J Sex Med 2010;7:2077–2085. [ABSTRACT FROM AUTHOR]

Introduction. Transforming growth factor-beta1 (TGF-β1) contributes to the pathogenesis of Peyronie's disease (PD). Pentoxifylline (PTX) antagonizes the effects of TGF-β1 and has been utilized in our clinic for the management of PD although the mechanisms of action are not entirely clear. Aim. We studied cell-signaling pathways through which TGF-β1 and PTX mediate collagen metabolism, elastin expression, and elastogenesis in tunica albuginea-derived fibroblasts (TADFs). Methods. TADFs from men with and without PD were cultured and treated with TGF-β1 and PTX as monotherapy at differing concentrations and time points. Combination treatment (TGF-β1 followed by PTX and vice versa) was also investigated. Main Outcome Measures. Reverse-transcription polymerase chain reaction and Western blotting were utilized to assess differences in elastin metabolism and cellular signaling between groups. Alpha-1 antitrypin (AAT1) expression was assayed. Results. At doses greater than 0.1 ng/Ml, TGF-β1 increased messenger ribonucleic acid (mRNA) and protein expression of elastin in a time-dependent fashion in TADF. PTX did not interfere with TGF-β1 mediated upregulation of elastin mRNA and protein in TADF. However, pretreatment of TADF with PTX was associated with decreased expression of AAT1, decreased activity of the Smad1/5 pathway, and enhanced phosphorylation of the inhibitory Smad6. Conclusion. Expression of elastin mRNA and protein is upregulated in TADF by TGF-β1. PTX has no effect on elastin production but attenuates elastogenesis in TADF through an AAT1-related mechanism. Lin G, Shindel AW, Banie L, Ning H, Huang YC, Liu G, Lin CS, and Lue TF. Pentoxifylline attenuates TGF-β1-stimulated elastogenesis in human tunica albuginea-derived fibroblasts Part 2: interference in a TGF-β1/Smad-dependent mechanism and downregulation of aat1. J Sex Med 2010;7:1787–1797. [ABSTRACT FROM AUTHOR]

The article presents a study which aims to examine the effectiveness of rivaroxaban to treat livedoid vasculopathy (LV). Several treatments, which include pentoxifylline, systemic corticosteroid and aspirin, but skin lesions waned and waxed without complete remission. Rivaroxaban treatment led in clinical improvement in all three patients.

Background Pemphigus vulgaris (PV) represents a potentially life-threatening autoimmune blistering disease in which IgG autoantibodies are directed against cell–cell adhesion molecules. Tumour necrosis factor (TNF)-α has been suggested to have a possible role in the mechanism underlying acantholysis. Objectives This comparative double-blinded study was carried out to estimate the use of both sulfasalazine (SSZ) and pentoxifylline (PTX) (low-cost anti-TNF drugs) as an adjuvant therapy for PV. Methods The study included 64 patients with PV: 42 patients received the full treatment regimen (with SSZ and PTX) and 22 patients followed the same regimen except they received placebo instead of PTX and SSZ. Five healthy subjects were included as controls. Serum samples were taken to measure TNF-α levels in the control group and before starting treatment in both the patient groups and this was repeated every 2 weeks for 8 weeks; a clinical assessment was made every week for all the patients. Results The serum level of TNF-α was statistically higher in both groups of patients than in the healthy individuals. There was a statistically significant decrease in the serum levels of TNF-α in patients in group 1 compared with those in group 2 at 6 and 8 weeks. There was also a significant clinical improvement in patients in group 1 compared with those in group 2. Conclusion The use of PTX and SSZ as adjuvant therapy in the treatment of PV induced a faster and more significant decrease in the serum level of TNF-α, and this decrease was associated with rapid clinical improvement. [ABSTRACT FROM AUTHOR]

Aim: The biotransformation of pentoxifylline (PTX), propentofylline (PPT) and their racemic hydroxy metabolites ((±)-OHPTX and (±)-OHPPT) by using the fungus Cunninghamella echinulata NRRL 1384. Methods and Results: A fungus Cunninghamella echinulata NRRL 1384 was used to catalyse the ( S)-selective oxidation of the racemic hydroxy metabolites: (±)-OHPTX and (±)-OHPPT and for reduction of PTX and PPT. The first oxidation step appears to be selective and relatively fast while the second reduction step is slower and more selective with PTX. Modifications involving supplementing the bioconversion with glucose give yields and enantiomeric excess (ee) values similar to those obtained without glucose. Conclusions: The bioconversion of (±)-OHPTX gave an ( R)-enantiomer (LSF-lisofylline) with a higher enantiopurity (maximum approximately 93% ee) compared to the bioconversion of (±)-OHPPT, when the maximum ee value for ( R)-OHPPT was recorded at 83%. Significance and Impact of the Study: The conversion of (±)-OHPTX and (±)-OHPPT using Cunninghamella echinulata can be recognized as a process, which may be recommended as an alternative to the methods used to obtain ( R)-OHPTX and ( R)-OHPPT. [ABSTRACT FROM AUTHOR]

Abstract: Background: The pathogenesis of the post cardiopulmonary bypass (CPB) organ dysfunction syndrome is complex, with inflammation being an important component. The purpose of this prospective, randomized and controlled study was to evaluate the effect of a single dose of pentoxifylline (PTX) prior to CPB on high dependency unit time. Materials and methods: We studied 39 patients undergoing aorto-coronary bypass surgery with CPB. Patients received either 5mgkg−1 PTX after induction of anaesthesia or saline as placebo. Haemodynamics, parameters of pulmonary function and plasma levels of tumour necrosis factor α (TNFα) and C-reactive protein (CRP) were measured after the induction of anaesthesia (pre-CPB) and after weaning from CPB (post-CPB), 1h after the admission to the intensive care unit (ICU) and on the morning of the first postoperative day (1 POD), respectively. In addition, ventilation time and the high dependency unit time, i.e. the time till transferral to a peripheral ward, were documented. Results: Patients in the PTX group had lower TNFα values (6.3ngml−1 (4/8.2) vs 9.1ngml−1 (6.5/13.7)) (median (25%/75%), p =0.021), lower systolic (28±7mmHg vs 35±9mmHg, mean±SD, p =0.011) and mean pulmonary artery pressures (21±5 vs 26±6mmHg, p =0.017) after admission to the ICU than control patients. Haemodynamics and pulmonary function parameters did not differ. There was a trend towards earlier weaning from the respirator in the PTX group (10.0±3.5h) (min/max: 4/16; confidence interval (ConF): 1.8h) than the control group (12.3±4.2h) (min/max: 5–24; ConI: 2.4h) (p =0.077). Patients treated with PTX could be transferred to a peripheral ward about 24h earlier than control patients (95±35h, min/max: 32/190h; ConI: 17h; 119±29h, min/max: 66/165h; ConI: 16h) respectively; p =0.037). Conclusion(s): A single dose of PTX prior to CPB was able to reduce plasma levels of TNFα. In this descriptive study, there was a trend towards reduced duration of ventilation and the high dependency unit time, i.e. the time till transferral to a peripheral ward was shortened. [Copyright &y& Elsevier]

The aim of this study was to develop pharmacokinetic models for pentoxifylline (PTX) and the R(−)-enantiomer of the PTX metabolite 1, lisofylline (LSF), in order to identify some factors influencing the absorption of these compounds from the intestines and to clarify mechanisms involved in their non-linear pharmacokinetics. Serum samples were collected after oral and intravenous administration of PTX and LSF to male CD-1 mice at two different doses. In addition, both compounds under investigation were coadministered with a modulator of drug transporters, verapamil, and an inhibitor of cytochrome P450 (CYP) 3A4, ketoconazole. Pharmacokinetic analysis revealed that a one-compartment model with Michaelis–Menten type absorption and elimination best described the pharmacokinetics of PTX, whereas the LSF concentration–time data were adequately fitted to a two-compartment model with a first-order absorption and Michaelis–Menten type elimination process. Both coadministered compounds significantly decreased the area under the concentration–time curve from 0 to 60 min calculated for PTX and increased the value of this parameter for LSF. The results of this study indirectly suggest that saturation of drug transport across intestinal cells and elimination from the central compartment may be responsible for the non-linear pharmacokinetics of PTX, whereas in the case of LSF, the dose dependency in the pharmacokinetics is solely related to the elimination from the central compartment. It seems that the observed changes in PTX and LSF concentrations after coadministration with verapamil and ketoconazole may be clinically significant, especially after chronic treatment, however further studies are necessary to assess the importance of these interactions in humans. [ABSTRACT FROM AUTHOR]

Background: sepsis and infection are among the leading causes of death world-wide. The annual burden of sepsis in high income countries is rising with mortality of 40%. Despite these figures from industrialized countries, the largest part of the global sepsis burden occurs in middle and low-income countries, 90% of the world wide deaths frompneumonia, meningitis or other infections occur in less developed countries. Aim of the Work: to evaluate the therapeutic efficiency of pentoxifylline as an adjuvant therapy in treatment of severe sepsis and its effect in multiple organ dysfunction and mortality in septic patients. Materials and Methods: this is a randomized double blinded prospective study conducted from January 2015 to March 2016 included total sample size 52 cases (we used organ dysfunction as a primary outcome with proposed large effect size (0.8) and alfa=0.05 and power=0.80, so, 26 cases were needed in each group). Results: we included 52 patients with sepsis who were divided in 1: 1 ratio to receive pentoxifylline or not. The average age of the included patients was almost 53 years, with no statistically significant different between both groups (p=0.902); while the majority of the included patients were males, with no significant difference between both groups (p=0.99). The mean weight was similar between both groups (84.50 ± 11.25 vs. 83.65 ± 10.54 years; p=0.78) and chest disorders were the main cause of sepsis in both groups. Conclusion: we concluded that PTX as an adjuvant therapy had no significant influence on the SOFA score, lactate level, CRP level, and pro-calcitonin level compared to control. Moreover, there were no statistically significant differences in terms of length of hospital stay, need for HD, need for vasopressor and inotropic, need for MV, and mortality rate. Further large clinical trials are recommended to assess the effectiveness of PTX especially with regards to organ failure, survival, and dose dependency. [ABSTRACT FROM AUTHOR]

We tested the combination of phosphodiesterase (PDE) 3 and PDE4 inhibitors as an interventional approach to prevent the development of brain damage after Shiga toxin (Stx)-producing Escherichia coli (STEC) infection, using mice with protein calorie malnutrition. The combination consisted of pentoxifylline and rolipram; the dose of each inhibitor was 7.5 mg/kg. Treatment with this combination, which was administered intraperitoneally twice daily at 12-h intervals, increased serum concentrations of each inhibitor to >2 μg/mL and afforded significant levels of protection when it was continued for 3 days, starting on day 2 (95% survival rate; P < .001) or day 3 (63% survival rate; P < .01) of infection. The treatment reduced plasma levels of Stx2; consequently, immunoreactions of Stx2 were not found in the brain, and survivors did not show neurologic symptoms. Protection was associated with decreased levels of tumor necrosis factor (TNF)-α and increased production of interleukin-10 in serum, the brain, and the cecum. Although the combination at doses >2 μg/ mL reduced Gb3 content of and Stx2 binding to Caco-2 cells, its ability to suppress production of TNF-a seemed to be more important for the decrease in cell-bound Stx2 in intestinal epithelial cells. Therefore, the combination of PDE3 and PDE4 inhibitors might be used as an interventional approach to prevent brain damage caused by STEC infection. [ABSTRACT FROM AUTHOR]

Chronic inflammation associated with cachexia, weight loss, fever and arthralgia is the hallmark of advanced mycobacterial diseases. These symptoms are attributed to the chronic stimulation of tumour necrosis factor (TNF)- α. Mycobacterial components directly stimulate adherent cells to secrete TNF- α. We have shown recently that IgG1 antimycobacterial antibodies play a role in augmenting TNF- α in purified protein derivative (PPD)-stimulated adherent cells from non-BCG-vaccinated donors. We now show that IgG1 antibodies can also augment TNF- α expression in stimulated adherent cells obtained from BCG-vaccinated donors and this augmentation is not linked to interleukin (IL)-10 secretion. In addition IgG1 antimycobacterial antibodies can reverse the effect of TNF- α blockers such as pentoxifylline and thalidomide. These studies therefore have clinical implications for anti-inflammatory drug treatments which are used increasingly to alleviate symptoms associated with chronic inflammation. [ABSTRACT FROM AUTHOR]

Objective: Previous studies have suggested reductions in lung reperfusion injury when initial reperfusion is undertaken with the addition of pharmacological modulators. We investigated three pharmacological agents in a porcine model of left single lung transplantation to determine the effect on lung compliance and its relationship with the expression of the cytokine, interleukin-8 (IL-8). Methods: Donor lungs were preserved with modified Euro-Collins for a mean ischaemic time of 18.6 h. Pulmonary venous oxygenation, lung compliance and IL-8 expression were assessed over a 12-h period. Group A (n=5) was a control group with no interventions added, Group B was reperfused with the addition of intravenous inositol hexakisphosphate (InSP6) (0.02 mg/kg per min), Group C received the nitric oxide donor, 3-morpholinosydnonimine (SIN-1) (0.02 mg/kg per min) and Group D received intravenous Pentoxifylline (2 mg/kg per h). All interventions were administered at a pulmonary artery pressure of 20 mmHg. Results: Group D yielded the best oxygenation (P=0.0041) while Groups B and C were similar. All were superior to Group A (P<0.001). Lung compliance was significantly improved in Groups B, C and D compared to group A. In Group D, the greatest improvements in lung compliance were observed (P<0.0001). Similar observations were seen with regard to pulmonary vascular resistance. IL-8 expression was delayed until after 30 min of reperfusion in Group D, but was evident after 10 min in all the other groups. This correlates with the compliance and oxygenation data. Conclusions: The addition of InSP6 or SIN-1 at reperfusion significantly attenuates reperfusion injury compared with controls and improves lung compliance. The unique comparison with Pentoxifylline afforded by this study indicates that at the doses studied Pentoxifylline appears to be superior, correlating with a greater inhibition of IL-8 expression. [Copyright &y& Elsevier]

Coexposure to small, noninjurious doses of the pyrrolizidine alkaloid phytotoxin monocrotaline (MCT) and bacterial lipopolysaccharide (LPS) results in synergistic hepatotoxicity. Both centrilobular and midzonal liver lesions occur and are similar to those seen from large, toxic doses of MCT and LPS, respectively. The nature of the lesions in vivo and results from studies in vitro suggest that injury is mediated indirectly rather than from a simple interaction of MCT and LPS with hepatic parenchymal cells. Accordingly, the role of inflammatory factors, such as Kupffer cells and TNF-α, in the development of MCT/LPS-induced liver injury was investigated. In Sprague-Dawley rats, MCT (100 mg/kg, ip) was administered 4 h before LPS (7.4 × 106 EU/kg, iv). Pretreatment of these animals with gadolinium chloride, an inhibitor of Kupffer cell function, attenuated liver injury 18 h after MCT administration. An increase in plasma TNF-α preceded the onset of hepatic parenchymal cell injury, raising the possibility that this inflammatory cytokine contributes to toxicity. Either pentoxifylline, an inhibitor of cellular TNF-α synthesis, or anti-TNF-α serum coadministered to MCT/LPS-treated animals significantly attenuated liver injury. These results suggest that Kupffer cells and TNF-α are important mediators in the synergistic hepatotoxicity resulting from MCT and LPS coexposure. [ABSTRACT FROM PUBLISHER]

SUMMARY The effect of phosphodiesterase-inhibiting anti-inflammatory drug pentoxifylline (PTX) on LPS-induced IL-18 synthesis and IL-18-mediated IFN-gamma-induction were investigated. In a dose-dependent manner PTX inhibited production of IL-18 in LPS-treated cultures of murine spleen cells and bone marrow-derived macrophages. Similarly, PTX treatment significantly reduced blood IL-18 levels and expression of spleen IL-18 mRNA in LPS-challenged mice. The inhibitory effect of PTX was specific for IL-18, since LPS-induced IL-12 p40 release was not suppressed either in splenocyte cultures or blood of LPS-injected animals. Synergistic induction of IFN-gamma by combined IL-12/IL-18 treatment was also inhibited by PTX in vitro and in vivo. Experiments with IL-12 pretreatment of splenocytes, followed by IL-18 stimulation, revealed that PTX suppressed both IL-12 and IL-18 signals responsible for IFN-gamma induction. These results suggest that interference with IL-18 synthesis and IFN-gamma-inducing activity might contribute to anti-inflammatory actions of PTX. [ABSTRACT FROM AUTHOR]

Background. Kidneys that progress to end‐stage renal failure are almost invariably characterized by the presence of tubulointerstitial fibrosis. Therapeutic interventions to halt the progressive deterioration of renal function are still limited. Pentoxifylline, pentifylline, and γ‐interferon have shown a potential benefit in the treatment of fibrotic processes in the skin and lung. Thus, the aim of the present study was the analysis of potential anti‐fibrotic effects of these substances on human kidney fibroblasts in vitro. [ABSTRACT FROM PUBLISHER]

Small amounts of exogenous lipopolysaccharide (LPS) (10 ng/kg–100 μg/kg) enhance the hepatotoxicity of allyl alcohol in male Sprague-Dawley rats. This augmentation of allyl alcohol hepatotoxicity appears to be linked to Kupffer cell function, but the mechanism of Kupffer cell involvement is unknown. Since Kupffer cells produce tumor necrosis factor-alpha (TNFα) upon exposure to LPS, and this cytokine has been implicated in liver injury from large doses of LPS, we tested the hypothesis that TNFα contributes to LPS enhancement of allyl alcohol hepatotoxicity. Rats were treated with LPS (10–100 μg/kg iv) 2 h before allyl alcohol (30 mg/kg ip). Co-treatment with LPS and allyl alcohol caused liver injury as assessed by an increase in activity of alanine aminotransferase in plasma. Treatment with LPS caused an increase in plasma TNFα concentration, which was prevented by administration of either pentoxifylline (PTX) (100 mg/kg iv) or anti-TNFα serum (1ml/rat iv) one h prior to LPS. Only PTX protected rats from LPS-induced enhancement of allyl alcohol hepatotoxicity; anti-TNFα serum had no effect. Exposure of cultured hepatocytes to LPS (1–10 μg/ml) or to TNFα (15–150 ng/ml) for 2 h did not increase the cytotoxicity of allyl alcohol (0.01–200 μM). These data suggest that neither LPS nor TNFα alone was sufficient to increase the sensitivity of isolated hepatocytes to allyl alcohol. Furthermore, hepatocytes isolated from rats treated 2 h earlier with LPS (i.e., hepatocytes which were exposed in vivo to TNFα and other inflammatory mediators) were no more sensitive to allyl alcohol-induced cytotoxicity than hepatocytes from naïve rats. These data suggest that circulating TNFα is not involved in the mechanism by which LPS enhances hepatotoxicity of allyl alcohol and that the protective effect of PTX may be due to another of its biological effects. [ABSTRACT FROM PUBLISHER]

Background and Aim: Diabetic neuropathy (DN) is the most common diabetic complication, which has a lifetime prevalence of about 50%. About 20 to 30% of patients with DN suffer from neuropathic pain. This study was designed to investigate the role of early and late treatment of pentoxifylline (PTX) in management of diabetic neuropathic pain (DNP). Method: Diabetic rats were administered PTX (50 and 200mg/ kg/day, in drinking water) either one week after STZ injection and for 7 weeks or 6 weeks after STZ injection and for 2 weeks. Mechanical allodynia were assessed weekly, Iba-1 and GFAP immunorectivity, spinal NFkB & spinal sciatic TNF-α were estimated at the end of the study. Epidermal thickness of the food pad and Na+/K+-ATPase activity in sciatic nerve were measured as an outcome measure for predegenerative markers of DN. Results: The results of the present study suggest that activated microglia and not astrocytes are involved in the development of experimental diabetic neuropathy. PTX inhibit neuroimmune activation of microglia, reduce the levels of proinflammatory cytokines and improve epidermal thickness of the food pad and Na+/K+-ATPase activity in sciatic nerve. Only PTX 200 mg/kg/ day when administered early and late treatment in diabetic rats produced antiallodynic effect. Conclusion: PTX is a fundamental drug whose antiallodynic effect depends on the pathogenetic mechanisms and has the ability to halt or inhibit the progression of the disease. The earlier the use of PTX in the developmental phase of mechanical hyperalgesia the more the antiallodynic effect of the drug. [ABSTRACT FROM AUTHOR]

Increasing evidence has implicated TNF-α as a pivotal molecule involved in the systemic inflammatory manifestations of ENL, an acute inflammatory complication that may occur in the chronic course of leprosy. In the present study, the mechanism of action of pentoxifylline (PTX) as an alternative therapy for management of leprosy reactions has been evaluated. The effect of PTX on TNF-α production was examined in leprosy patients at the protein level and at the transcriptional level as well. Treatment of ENL patients with PTX (1200 mg daily) ameliorated the systemic symptoms and favoured the evolution of reactional leprosy lesions. Serum TNF-α was assayed before and during treatment with PTX in 15 patients. The increased TNF-α levels seen in the circulation during the reaction were dramatically reduced within 3–7 days of therapy. No significant effect on serum IL-6 was noted. In vitro TNF-α production was assayed upon culture stimulation with Mycobacterium leprae. A reduction of inducible TNF-α in peripheral blood mononuclear cells (PBMC) was seen after 1–2 weeks of in vivo administration of PTX. Furthermore, no effect of the drug on IL-10 secretion was detected in these cultures. A kinetic analysis of the expression of TNF-α and IL-6 mRNA at the site of leprosy lesion was performed in six reactional patients by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). The amount of TNF-α mRNA was increased in the tissue during ENL compared with before the reaction, and decreased thereafter following treatment for reaction (either PTX or thalidomide). These data suggest that PTX inhibits TNF-α production in ENL patients both in vivo and in vitro, and it may be useful in the treatment of leprosy patients undergoing ENL. [ABSTRACT FROM AUTHOR]

Dexamethasone appears to show some adverse side-effects as adjunctive anti-inflammatory agent in bacterial meningitis. For this reason, we tested the anti-inflammatory and neuroprotective effect of pentoxifylline administered 15 min before starting antibiotic treatment with ceftriaxone (n = 10) versus antibiotic therapy alone (n = 9) in the rabbit model of pneumococcal meningitis. Pentoxifylline lowered the medians of leucocyte density, tumour necrosis factor-alpha (TNF-α) and lactate in the cerebrospinal fluid (CSF), but only leucocyte migration into the subarachnoid space was significantly inhibited 8 h after initiation of therapy (P = 0.01). CSF protein, brain water content, and the entry of ceftriaxone into CSF were not influenced by pentoxifylline. The density of neuronal apoptoses in the dentate gyrus was slightly lower in animals receiving pentoxifylline than in those treated with ceftriaxone only. The median concentration of neuron-specific enolase in CSF was lower in the pentoxifylline-treated group, but the difference was not significant. In conclusion, pentoxifylline showed some anti-inflammatory activity in pneumococcal meningitis, but the substance failed significantly to reduce neuronal damage. [ABSTRACT FROM AUTHOR]

Cyclic nucleotide phosphodiesterase inhibitors, such as pentoxifylline, have been shown to beneficially influence a large number of inflammatory skin diseases. The biological effects of pentoxifylline on the production of proinflammatory cytokines, leukocyte–endothelial cell adhesion, chemokines and leukocyte–keratinocyte adhesion in skin inflammation are discussed. [ABSTRACT FROM AUTHOR]

The significance of vascular congestion in the pathogenesis of cisplatin acute renal failure (ARF) was studied in rats given pentoxifylline. Rats were administered single intraperitoneal doses of 1.0, 2.5, 5.0, and 10.0 mg/kg of cisplatin with 45 mg/kg of pentoxifylline or saline every 12 h for 3 days. Cisplatin caused dose-dependent declines in the mean inulin clearance values in the rat that were not attenuated with pharmacological doses of pentoxyfylline. There were no differences in histology, urinary electrolyte excretion rates, and serum creatinine values between cisplatin toxicity groups treated with saline or pentoxifylline. Erthrocyte congestion was studied with Cr-labelled erythrocytes in rats given single doses of 5 mg/kg of cisplatin with and without pentoxifylline in an attmpt to define the role of capillary sludging. The papilla, medulla, and cortex of kidneys of cisplatin-treated rats were markedly congested with Cr-erythrocytes; however, pentoxifylline treatment did not significantly reduce the congestion. These data suggest that although erythrocyte trapping is involved in cisplatin ARF, treatment with pharmacological doses of vascular decongestants does not fully attenuate the functional defect. [ABSTRACT FROM PUBLISHER]

A causal link between plasma fibrinogen levels and the risk of cardiovascular disease is now reasonably well established. Therefore the therapeutic lowering of fibrinogen has become a relevant area of research. Several options to achieve this aim have been reported in the literature. Changes in lifestyle can affect the fibrinogen level, of which smoking cessation is by far the most effective; weight or stress reduction or an increase in regular physical activity may have less pronounced effects; dietary changes appear to have even less effect, though a regular, moderate alcohol consumption may result in a small reduction. Many oral drugs have been shown to lower fibrinogen; however, the data should be viewed critically. In particular, the clinical situation in which a drug is administered must be considered and risk: benefit analyses should be performed before a drug is recommended for this indication. Among the oral fibrinogen-lowering drugs, fibrates rank first (e.g. bezafibrate has been reported to reduce increased fibrinogen by as much as 40%, and ticlopidine can induce a reduction of about 15% if fibrinogen was elevated at baseline). Whether concentration within the normal range can be altered by oral medication is less clear. Finally (and obviously), intravenous fibrinolytic agents or heparin-induced extracorporeal low-density lipoprotein precipitation will lower fibrinogen dramatically; yet these procedures are rarely indicated for this purpose alone. All options to lower fibrinogen also have prominent effects on other cardiovascular functions; thus, an intervention trial may not be the most appropriate method of testing the validity of the hypothesis of fibrinogen as a cardiovascular risk factor. [ABSTRACT FROM PUBLISHER]

Objective: The aim was to assess the role of neutrophils in anoxia-reoxygenation induced, neutrophil mediated damage to cardiac myocytes. Methods: Neonatal rat cardiac myocytes in primary monolayer cultures were exposed to a 2 h period of anoxia, and subsequently reoxygenated for 3 h. Neutrophils were added at the time of reoxygenation, and myocyte injury was determined by release of lactate dehydrogenase (LDH). Results: Neutrophils produced a dose dependent increase in myocyte LDH release. This effect was not enhanced by coincubation with a neutrophil activator (formyl-Met-Leu-Phe), or interleukine lα (IL-lα), although IL-lα increased anoxic myocyte damage. Exposure to supematants from anoxic, or anoxic-reoxygenated, myocytes increased LDH release from normoxic myocytes, and conditioning of these supematants by neutrophils further increased their cytotoxic potential. The anoxia-reoxygenation induced, neutrophil mediated LDH release was attenuated by some oxygen radical scavengers (superoxide dismutase, histidine, and desferrioxamine), but not others (catalase). Marked decrease in LDH release was also observed after addition of L-arginine, the substrate for synthesis of nitric oxide, along with the neutrophils at the time of reoxygenation. In addition, neutrophil mediated myocyte injury was attenuated by protease inhibitors (Eglin C and α2 macroglobulin), an anti-CD 18 monoclonal antibody, and the methylxanthine derivative pentoxifylline, respectively. Conclusions: The results indicate that neutrophils increase myocyte reoxygenation damage, and that reoxygenated cardiac myocytes release potent neutrophil stimulants and cytotoxic mediators. The anoxia-reoxygenation induced, neutrophil mediated myocyte damage is dependent on oxygen free radicals, proteases, and cellular adhesion, and stimulation of endogenous NO production may be protective in this model.Cardiovascular Research 1994;28:565-569 [ABSTRACT FROM PUBLISHER]

The efficacy and toxicity of certain antifungal agents may be related to their ability to induce the production of cytokines by mononuclear phagocytes. The capacity of incremental concentrations of fluconazole, 5-fluorocytosine (5-FC), amphotericin B (AmB), and liposomal AmB (LAB) to stimulate murine peritoneal and RAW 264.7 macrophages to secrete tumour necrosis factor alpha (TNF alpha) after 3, 6 and 24 h incubation was assessed by L929 cytotoxic bioassay. Fluconazole (2.5-40 mg/L) and 5-FC (25-100 mg/L) did not have a stimulatory effect. However, AmB (0.25-10 mg/L) elicited TNF alpha production by macrophages. This response was concentration-dependent, and peak TNF alpha levels were detected between 3 and 6 h. This effect was attenuated by incorporation of AmB into liposomal vesicles and by pretreating macrophages with pentoxifylline or dexamethasone. AmB I mg/L in combination with 1 x 10(6) cfu of Candida albicans stimulated peritoneal macrophages to produce similar quantities of TNF alpha as AmB alone, and two- to four-fold more TNF alpha than C. albicans alone. Thus, this study suggests that: (1) the immunomodulatory activity and toxicities of AmB, in part, may be attributed to the capacity of this drug to stimulate macrophages to secrete TNF alpha, (2) the TNF alpha that is produced by macrophages in response to AmB may have clinical relevance even in the face of C. albicans infection, and (3) the failure of fluconazole, 5-FC, and LAB to elicit a TNF alpha response may explain their improved side-effect profiles. [ABSTRACT FROM AUTHOR]

It is well established that endotoxin [lipopolysacharide (LPS)] induces pro-inflammatory cytokine production in monocytes, which is followed by secretion of the anti-inflammatory cytokine, IL-10. IL-10 down-regulates inflammatory response [tumor necrosis factor (TNF)-α, IL-1, IL-6, IL-8] as well as IL-10 synthesis itself. We wondered whether pro-inflammatory cytokines such as TNF-α may be involved in the regulation of human IL-10 synthesis. TNF-α induced IL-10 mRNA expression in a dose-dependent manner but no IL-10 protein in human peripheral blood mononuclear cells. Furthermore, LPS-induced IL-10 gene and protein expression was significantly inhibited by neutralizing anti-TNF-α mAb. On the basis of these results, we conclude that TNF-α is involved in the up-regulation of its antagonist IL-10. Paradoxically, drugs that effectively inhibit expression of TNF-α via the elevation of intracellular cAMP level (iloprost, pentoxifylline, prostaglandin E and 6,2--dlbutyryl cAMP) augmented the endotoxin-induced IL-10 synthesis at both protein and mRNA levels. In order to provide a basis for the analysis of the transcriptional regulation of the human IL-10 gene, we isolated a fragment of the human IL-10 gene containing 1308 bp of the 5' non-coding sequence. It shows remarkable homology to the mouse IL-10 promoter in regions that have been associated with transcriptional regulation, including a cAMP responsive element which could explain the cAMP-mediated effects. The lack of a NF-kB-like binding site in the human sequence suggests a NF-KB-independent mechanism of TNF-α-induced IL-10 gene activation. In summary, our data demonstrate that TNF-α and cAMP elevating mediators, via induction of IL-10, are part of a negative feedback circuit that controls acute inflammatory response. [ABSTRACT FROM PUBLISHER]

Sperm suspensions were prepared either by the 'swim-up' technique or by a Percoll gradient method before pentoxifylline was added to improve sperm motion characteristics. They were subsequently washed and then incubated with oocytes in in-vitro fertilization (IVF) programmes. The curvilinear velocity and lateral head displacement were approximately 20% higher in Percoll gradient-separated samples compared with samples prepared by the swim-up technique (P > 0.001), sperm motion characteristics being assessed by computer-assisted semen analysis. The dose-response study in which samples were separated by Percoll gradient/swim-up method showed that pentoxifylline gave maximum enhancement of sperm motion characteristics at a concentration of 2.8 mM/l, when the curvilinear velocity and lateral head displacement were significantly increased (P > 0.001). However, when pentoxifylline was removed by washing, the enhanced motion characteristics were reduced or lost in the process. Surprisingly, washing had a significant effect on the control samples, the motion characteristics being increased significantly (P > 0.001). This study casts doubt on the usefulness of pentoxifylline in IVF programmes. [ABSTRACT FROM AUTHOR]

Sperm suspensions were prepared either by the ‘swim-up’ technique or by a Percoll gradient method before pentoxifylline was added to improve sperm motion characteristics. They were subsequently washed and then incubated with oocytes in in-vitro fertilization (IVF) programmes. The curvilinear velocity and lateral head displacement were ∽20% higher in Percoll gradient-separated samples compared with samples prepared by the swim-up technique (P > 0.001), sperm motion characteristics being assessed by computer-assisted semen analysis. The dose-response study in which samples were separated by Percoll gradient/swim-up method showed that pentoxifylline gave maximum enhancement of sperm motion characteristics at a concentration of 2.8 mM/l, when the curvilinear velocity and lateral head displacement were significantly increased (P > 0.001). However, when pentoxifylline was removed by washing, the enhanced motion characteristics were reduced or lost in the process. Surprisingly, washing had a significant effect on the control samples, the motion characteristics being Increased significantly (P > 0.001). This study casts doubt on the usefulness of pentoxifylline in IVF programmes. [ABSTRACT FROM PUBLISHER]

Pentoxifylline, an inhibitor of cAMP phosphodiesterase activity, favours intracellular cAMP concentration increase. In-vitro treatment of semen with pentoxifylline leads to marked augmentation of sperm motility, enhancement of acrosome reaction, increase of sperm penetration into zona-free hamster oocytes, and protection of the sperm plasma membrane. Such properties indicate that the drug may be a useful tool for semen preparation in assisted reproduction, but its real effectiveness in improving fertilization rates is still uncertain, mainly in association with intrauterine insemination (IUI). Theoretically sperm motility should play an extremely important role for positive results in IUI. Therefore, a retrospective clinical trial was planned in order to evaluate whether addition of pentoxifylline to the previously standardized in-vitro treatment of semen had improved the percentage of pregnancies after homologous IUI. The study involved 55 sterile couples (33 classified infertile for male factor and 22 for other factors) who underwent a total of 150 cycles of homologous IUI: 101 for male factor infertility and 49 for other factors (anovulation n = 26, endometriosis n = 2, idiopathic n = 21). Out of the 101 cycles performed for male factor infertility, 61 underwent the standard preparation of semen and were followed by seven pregnancies (pregnancy rate = 11.5%) while 40 had a semen preparation with pentoxifylline addition and were followed by 11 pregnancies (pregnancy rate = 27.5%) with a significant difference between the two procedures (P < 0.05). Out of the 49 cycles carried out for factors different from male infertility, 10 underwent the standard preparation of semen and were followed by two pregnancies (pregnancy rate = 20.0%), while 39 had pentoxifylline addition and were followed by nine pregnancies (pregnancy rate = 23.1%). The difference between the two groups was not significant. Abortions and malformations were equally distributed in the standard treatment and in the pentoxifylline group. [ABSTRACT FROM AUTHOR]

In the presence of pentoxifylline, human spermatozoa are induced to increase certain motion characteristics; however, the role of this drug in fertilization remains equivocal. In this study, the influence of pentoxifylline on one aspect of fertilization, that is sperm-zona binding, has been examined. Results from a fluorescence label competitive zona binding (CZB) test showed that spermatozoa exposed to a pentoxifylline challenge of between 0.1 and 5 mM, which was curtailed after 1 h by washing, had a decreased (P < 0.01) ability to bind to intact zona compared with control spermatozoa. The washing procedures also removed (decrease P < 0.01 compared with peak values) some of the enhanced motion characteristics induced by pentoxifylline. These results were in contrast with those obtained using experimental conditions that maintained an increased curvilinear velocity (VCL) and lateral head displacement (ALH) (increase P < 0.001 above baseline controls) in the continued presence of pentoxifylline. Using a hemizona binding (HZB) assay, 3 mM pentoxifylline increased (P < 0.001) sperm-zona binding almost 20% above zona binding with unexposed control spermatozoa. It was concluded that, in the presence of pentoxifylline, there is increased sperm binding to the zona pellucida; however, if the drug is removed by washing, the sperm binding to the zona is decreased in concert with the removal of the enhanced motion characteristics. The application of zona solubilization by acidic conditions in a microchamber enabled the precise determination of sperm numbers in both of the sperm-zona binding assays, and the results demonstrated that a wide variation in sperm numbers was observed in each test, with 63-580 spermatozoa bound in the CZB assay and 56-1340 spermatozoa bound on a hemizona. [ABSTRACT FROM AUTHOR]

In the presence of pentoxifylline, human spermatozoa are induced to increase certain motion characteristics; however, the role of this drug in fertilization remains equivocal. In this study, the influence of pentoxifylline on one aspect of fertilization, that is spermzona binding, has been examined. Results from a fluorescence label competitive zona binding (CZB) test showed that spermatozoa exposed to a pentoxifylline challenge of between 0.1 and 5 mM, which was curtailed after 1 h by washing, had a decreased (P < 0.01) ability to bind to intact zona compared with control spermatozoa. The washing procedures also removed (decrease P < 0.01 compared with peak values) some of the enhanced motion characteristics induced by pentoxifylline. These results were in contrast with those obtained using experimental conditions that maintained an increased curvilinear velocity (VCL) and lateral head displacement (ALH) (increase P < 0.001 above baseline controls) in the continued presence of pentoxifylline. Using a hemizona binding (HZB) assay, 3 mM pentoxifylline increased (P < 0.001) spermzona binding almost 20% above zona binding with unexposed control spermatozoa. It was concluded that, in the presence of pentoxifylline, there is increased sperm binding to the zona pelludda; however, if the drug is removed by washing, the sperm binding to the zona is decreased in concert with the removal of the enhanced motion characteristics. The application of zona solubilization by acidic conditions in a microchamber enabled the precise determination of sperm numbers in both of the spermzona binding assays, and the results demonstrated that a wide variation in sperm numbers was observed in each test, with 63–580 spermatozoa bound in the CZB assay and 56–1340 spermatozoa bound on a hemizona. [ABSTRACT FROM PUBLISHER]

In this study, human spermatozoa obtained from donors (n = 15) with normal semen characteristics were cryopreserved in human sperm preservation medium, supplemented with the phosphodiesterase inhibitor pentoxifylline at concentrations of 0, 1, 3 and 10 mM. The effect of pentoxifylline on cryopreserved spermatozoa was determined by monitoring changes in sperm motility and acrosome morphology by labelling the spermatozoa with fluorescein-conjugated concanavalin A lectin. Cryoprotectant supplemented with 1 mM pentoxifylline was found to improve post-thaw progressive motility from 15.3 +/- 2.4 (control) to 23.1 +/- 3.8% (P < 0.01), and total motility from 27.4 +/- 3.3 (control) to 38.2 +/- 3.9% (P < 0.05) without reducing the percentage of spermatozoa with normal acrosomal regions, and so appears useful for cryopreservation purposes. The beneficial effects of 1 mM pentoxifylline on sperm motility were shown to be maintained post-thaw over a 6 h time course. Cryoprotectant supplemented with 3 mM pentoxifylline was found to improve only post-thaw progressive motility, from 15.3 +/- 2.4 (control) to 20.7 +/- 3.0% (P < 0.05). However, cryopreservation in the presence of 10 mM pentoxifylline was found to have a significantly (P < 0.01) detrimental effect on acrosome morphology post-thaw, reducing it from 29.0 +/- 2.0 (control) to 21.0 +/- 2.4% without affecting sperm motility. This suggests that assessment of the acrosomal region may indicate subtle deleterious effects of cryoprotectant supplements that cannot be determined from post-thaw motility assessments alone. These findings differ from previous studies in that a lower concentration of pentoxifylline (1 mM) was found to be optimal for cryopreservation purposes. [ABSTRACT FROM AUTHOR]

In this study, human spermatozoa obtained from donors ( = 15) with normal semen characteristics were cryopreserved in human sperm preservation medium, supplemented with the phosphodiesterase inhibitor pentoxifylline at concentrations of 0, 1, 3 and 10 mM. The effect of pentoxifylline on cryopreserved spermatozoa was determined by monitoring changes in sperm motility and acrosome morphology by labelling the spermatozoa with fluorescein-conjugated concanavalin A lectin. Cryoprotectant supplemented with 1 mM pentoxifylline was found to improve post-thaw progressive motility from 15.3 ± 2.4 (control) to 23.1 ± 3.8% ( < 0.01), and total motility from 27.4 ± 3.3 (control) to 38.2 ± 3.9% ( < 0.05) without reducing the percentage of spermatozoa with normal acrosomal regions, and so appears useful for cryopreservation purposes. The beneficial effects of 1 mM pentoxifylline on sperm motility were shown to be maintained post-thaw over a 6 h time course. Cryoprotectant supplemented with 3 mM pentoxifylline was found to improve only post-thaw progressive motility, from 15.3 ± 2.4 (control) to 20.7 ± 3.0% ( < 0.05). However, cryopreservation in the presence of 10 mM pentoxifylline was found to have a significantly ( < 0.01) detrimental effect on acrosome morphology post-thaw, reducing it from 29.0 ± 2.0 (control) to 21.0 ± 2.4% without affecting sperm motility. This suggests that assessment of the acrosomal region may indicate subtle deleterious effects of cryoprotectant supplements that cannot be determined from post-thaw motility assessments alone. These findings differ from previous studies in that a lower concentration of pentoxifylline (1 mM) was found to be optimal for cryopreservation purposes. [ABSTRACT FROM PUBLISHER]

In the presence of pentoxifylline, spermatozoa can be induced to increase certain motion characteristics. This drug capability has been used to study the effect when applied directly on semen. An equal volume of pentoxifylline was added to semen, which was then incubated for 1 h before processing. Sperm motion was assessed employing computer-assisted semen analysis. The results showed that pentoxifylline increased curvilinear velocity, straight line velocity and lateral head displacement, the latter effect being concentration-dependent over the entire range of concentrations tested (r = 0.93, P < 0.0001). With a high concentration of pentoxifylline, spermatozoa exhibited characteristics consistent with hyperactive-like motion. Semen characteristics showed marked interindividual variation, ranging from 0 to > 40% response to 6 mM pentoxifylline challenge. Some 10% of patients showed little or no response to pentoxifylline. The sum of the percentage changes in curvilinear and straight line velocity, lateral head displacement and manual sperm count for each dose group was used to produce the stimulation index, measuring the overall response of spermatozoa to the drug. This stimulation index showed that the most effective concentration was 6 mM pentoxifylline, considerably higher than the 3.6 mM pentoxifylline used commonly for separated spermatozoa. [ABSTRACT FROM AUTHOR]

In the presence of pentoxifylline, spermatozoa can be induced to increase certain motion characteristics. This drug capability has been used to study the effect when applied directly on semen. An equal volume of pentoxifylline was added to semen, which was then incubated for 1 h before processing. Sperm motion was assessed employing computer-assisted semen analysis. The results showed that pentoxifylline increased curvilinear velocity, straight line velocity and lateral head displacement, the latter effect being concentration-dependent over the entire range of concentrations tested ( = 0.93, < 0.0001). With a high concentration of pentoxifylline, spermatozoa exhibited characteristics consistent with hyperactive-like motion. Semen characteristics showed marked inter-individual variation, ranging from 0 to >40% response to 6 mM pentoxifylline challenge. Some 10% of patients showed little or no response to pentoxifylline. The sum of the percentage changes in curvilinear and straight line velocity, lateral head displacement and manual sperm count for each dose group was used to produce the stimulation index, measuring the overall response of spermatozoa to the drug. This stimulation index showed that the most effective concentration was 6 mM pentoxifylline, considerably higher than the 3.6 mM pentoxifylline used commonly for separated spermatozoa. [ABSTRACT FROM PUBLISHER]