Multiple pathological events in exercised dystrophic mdx mice are targeted by pentoxifylline: outcome of a large array of in vivo and ex vivo tests.

PubMed

Burdi, Rosa; Rolland, Jean-François; Fraysse, Bodvael; Litvinova, Karina; Cozzoli, Anna; Giannuzzi, Viviana; Liantonio, Antonella; Camerino, Giulia Maria; Sblendorio, Valeriana; Capogrosso, Roberta Francesca; Palmieri, Beniamino; Andreetta, Francesca; Confalonieri, Paolo; De Benedictis, Leonarda; Montagnani, Monica; De Luca, Annamaria

2009-04-01

The phosphodiesterases inhibitor pentoxifylline gained attention for Duchenne muscular dystrophy therapy for its claimed anti-inflammatory, antioxidant, and antifibrotic action. A recent finding also showed that pentoxifylline counteracts the abnormal overactivity of a voltage-independent calcium channel in myofibers of dystrophic mdx mice. The possible link between workload, altered calcium homeostasis, and oxidative stress pushed toward a more detailed investigation. Thus a 4- to 8-wk treatment with pentoxifylline (50 mg x kg(-1) x day(-1) ip) was performed in mdx mice, undergoing or not a chronic exercise on treadmill. In vivo, the treatment partially increased forelimb strength and enhanced resistance to treadmill running in exercised animals. Ex vivo, pentoxifylline restored the mechanical threshold, an electrophysiological index of calcium homeostasis, and reduced resting cytosolic calcium in extensor digitorum longus muscle fibers. Mn quenching and patch-clamp technique confirmed that this effect was paralleled by a drug-induced reduction of membrane permeability to calcium. The treatment also significantly enhanced isometric tetanic tension in mdx diaphragm. The plasma levels of creatine kinase and reactive oxygen species were both significantly reduced in treated-exercised animals. Dihydroethidium staining, used as an indicator of reactive oxygen species production, showed that pentoxifylline significantly reduced the exercise-induced increase in fluorescence in the mdx tibialis anterior muscle. A significant decrease in connective tissue area and profibrotic cytokine transforming growth factor-beta(1) was solely found in tibialis anterior muscle. In both diaphragm and gastrocnemius muscle, a significant increase in neural cell adhesion molecule-positive area was instead observed. This data supports the interest toward pentoxifylline and allows insight in the level of cross talk between pathogenetic events in workloaded dystrophic muscle.

Pentoxifylline attenuates cytokine stress and Fas system in syngeneic liver proteins induced experimental autoimmune hepatitis.

PubMed

Hendawy, Nevien

2017-08-01

Apoptosis is a hallmark in the pathogenesis of autoimmune hepatitis (AIH). Cytokine stresses and extrinsic apoptotic pathway have been implicated in this type of hepatic injury. Pentoxifylline plays an important role in controlling inflammation and apoptosis in different autoimmune diseases. To assess the protective effect of pentoxifylline for 30days against pro-inflammatory cytokines as tumor necrosis factor-alpha (TNF-α), interferon-gamma (INF-γ) and mediators of extrinsic apoptotic pathway involving TNF receptor 1 (TNFR1) and its ligand TNF-α and Fas receptor and its ligand (FasL) in experimental autoimmune hepatitis (EAH) model. EAH was induced by intraperitoneal injection of syngeneic liver antigen emulsified in complete Freund's adjuvant (CFA) in male C57BL/6 mice. Five groups of mice were used: two control groups; Control PBS group and Control CFA group, EAH group and two EAH+pentoxifylline treated groups in doses (100 or 200mg/kg/d, given by oral gavage). Serum transaminase, pro-inflammatory cytokines (TNF-α and interferon-γ) and hepatic caspase-8 and 3 activities were evaluated. Signs of autoimmune hepatitis were confirmed by liver histology. In addition, hepatic TNFR1, Fas and FasL mRNA expression were assayed. Serum transaminase levels and signs of AIH observed in EAH mice were significantly reduced by pentoxifylline. Upregulated serum TNF-α, IFN-γ, hepatic caspase-8 and 3 activities and TNFR1, Fas and FasL mRNA expression in liver tissues in EAH group were significantly downregulated by pentoxifylline. Pentoxifylline protects against syngeneic liver antigen induced hepatitis and associating apoptosis through attenuating the exaggerated cytokine release and extrinsic apoptotic pathway. Thus, this may represent a new therapeutic strategy for hepatitis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Controlled study on the effect of pentoxifylline and an ergot alkaloid derivative on regional cerebral blood flow in patients with chronic cerebrovascular disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hartmann, A.; Tsuda, Y.

Regional cerebral blood flow (rCBF) in 90 patients with CBF decreased due to vascular diseases was studied by using the xenon 133 inhalation technique and a 32-detector setup. Whereas 30 patients received their standard basic therapy only and were regarded as controls, 30 others received 3 x 2 mg/day of an ergot alkaloid (co-dergocrine mesylate), and 30 others received 3 x 400 mg pentoxifylline (slow-release formulation)/day orally. Therapy was performed for eight weeks and CBF measured before start of treatment, after a four-week treatment period, and at the end of the study. CBF did not change significantly in the controlmore » group; both the pentoxifylline and the ergot alkaloid group presented with a significant increase in the CBF. This positive effect was significantly more pronounced in the pentoxifylline group and affected more ischemic than other brain tissues. In addition, symptoms like sleep disturbances, vertigo, and tinnitus improved significantly during the pentoxifylline observation period.« less

Effect of thalidomide and pentoxifylline on experimental autoimmune encephalomyelitis (EAE).

PubMed

Corrêa, José Otávio do Amaral; Aarestrup, Beatriz Julião Vieira; Aarestrup, Fernando Monteiro

2010-11-01

Autoimmune encephalomyelitis (EAE) in Lewis rats is a classical experimental model of demyelinating inflammatory disease of the central nervous system. EAE is widely accepted for study of immune-inflammatory mechanisms in the CNS related to multiple sclerosis (MS) due to similar clinical evolution. In the present study we investigated the effects of Thalidomide and pentoxifylline during EAE development in Lewis rats. EAE was induced in Lewis rats and treatment with Thalidomide or pentoxifylline was performed. Clinical evaluation was carried out daily. Histopathological analysis of the brain tissue and spinal cord was performed. Griess method was used for determination of NO serum levels. TNF-alpha and IFN-gamma serum levels were investigated using ELISA method. Thalidomide and pentoxifylline treatment is associated with significant reduction of neuroinflammation in CNS. Serum levels of NO, IFN-gamma and TNF-alpha showed a marked reduction. Such findings were correlated with improvement of clinical symptoms, particularly in thalidomide treated rats. Taken together the data suggested that thalidomide and pentoxifylline may be therapeutic options for the treatment of MS, however further experiments must be performed to investigate this hypothesis. Copyright © 2010 Elsevier Inc. All rights reserved.

Lipoic acid and pentoxifylline mitigate nandrolone decanoate-induced neurobehavioral perturbations in rats via re-balance of brain neurotransmitters, up-regulation of Nrf2/HO-1 pathway, and down-regulation of TNFR1 expression.

PubMed

Ahmed, Maha A E; El-Awdan, Sally A

2015-07-01

Behavioral perturbations associated with nandrolone decanoate abuse by athletes and adolescents may be attributed to oxidative stress and inflammation. However, the underlying mechanisms are not yet fully explored. On the other hand, the natural antioxidant lipoic acid can pass the blood brain barrier and enhance Nrf2/HO-1 (nuclear factor erythroid-2 related factor 2/heme oxygenase-1) pathway. In addition, the phosphodiesterase-IV inhibitor xanthine derivative pentoxifylline has a remarkable inhibitory effect on tumor necrosis factor-alpha (TNF-α). Therefore, this study aimed at investigation of the possible protective effects of lipoic acid and/or pentoxifylline against nandrolone-induced neurobehavioral alterations in rats. Accordingly, male albino rats were randomly distributed into seven groups and treated with either vehicle, nandrolone (15mg/kg, every third day, s.c.), lipoic acid (100mg/kg/day, p.o.), pentoxifylline (200mg/kg/day, i.p.), or nandrolone with lipoic acid and/or pentoxifylline. Rats were challenged in the open field, rewarded T-maze, Morris water maze, and resident-intruder aggression behavioral tests. The present findings showed that nandrolone induced hyperlocomotion, anxiety, memory impairment, and aggression in rats. These behavioral abnormalities were accompanied by several biochemical changes, including altered levels of brain monoamines, GABA, and acetylcholine, enhanced levels of malondialdehyde and TNF-α, elevated activity of acetylcholinesterase, and up-regulated expression of TNF-α receptor-1 (TNFR1). In addition, inhibited catalase activity, down-regulated Nrf2/HO-1 pathway, and suppressed acetylcholine receptor expression were observed. Lipoic acid and pentoxifylline combination significantly mitigated all the previously mentioned deleterious effects mainly via up-regulation of Nrf2/HO-1 pathway, inhibition of TNF-α and down-regulation of TNFR1 expression. In conclusion, the biochemical and histopathological findings of this study revealed the protective mechanisms of lipoic acid and pentoxifylline against nandrolone-induced behavioral changes and neurotoxicity in rats. Copyright © 2015 Elsevier Inc. All rights reserved.

Delayed toxicity of two chitinolytic enzyme inhibitors (psammaplin a and pentoxifylline) against eastern subterranean termites (Isoptera: Rhinotermitidae).

PubMed

Hiusen, Timothy J; Kamble-Shripat, T

2013-08-01

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. Concentration-dependent 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.

Function and culture requirements of snow leopard (Panthera uncia) spermatozoa in vitro.

PubMed

Roth, T L; Howard, J G; Donoghue, A M; Swanson, W F; Wildt, D E

1994-08-01

Electroejaculates from eight snow leopards were used to determine how the motility of spermatozoa was influenced by (i) type of media (Ham's F10, PBS, human tubal fluid or RPMI-1640); (ii) holding temperature (23 degrees C versus 37 degrees C); (iii) washing of spermatozoa and (iv) a sperm metabolic enhancer, pentoxifylline. The duration of sperm motility was assessed by evaluating samples in each treatment every hour for 6 h and a sperm motility index (a value combining percentage sperm motility and rate of forward progression) calculated. Spermatozoa from the Ham's F10, PBS and PBS plus pentoxifylline treatments were also co-incubated with zona-intact, domestic cat eggs that were fixed and evaluated for spermatozoa bound to the zona pellucida, penetrating the outer and inner layers of the zona pellucida and within the perivitelline space. During the 6 h co-incubation, the sperm motility index in PBS with pentoxifylline was greater (P < 0.05) than in PBS alone which, in turn, was greater (P < 0.05) than in the other three test media. Washing the spermatozoa enhanced (P < 0.05) motility in both PBS and PBS plus pentoxifylline relative to unwashed samples, but there was no effect (P > 0.05) of holding temperature. Pentoxifylline supplementation enhanced (P < 0.05) the proportion of cat eggs with bound, but not penetrated, snow leopard spermatozoa in the inner layer of the zona pellucida, and there were no spermatozoa in the perivitelline space.(ABSTRACT TRUNCATED AT 250 WORDS)

Compromised breast flap treated with leech therapy, hyperbaric oxygen, pentoxifylline and topical nitroglycerin: A case report.

PubMed

Moffat, Andrew D; Weaver, Lindell K; Tettelbach, William H

2015-01-01

Hyperbaric oxygen (HBO2) is often indicated in compromised surgical flaps. Although limited to animal models and human case reports, the utilization of leech therapy (Hirudo medicinalis) with HBO2 provides better outcomes than each modality alone. Topical nitroglycerin and pentoxifylline are also frequently used adjunctively for compromised flaps. We present a case of successful breast flap salvage utilizing a combination of leech therapy, HBO2, topical nitroglycerin and pentoxifylline. A 34-year-old female, one day post-status cosmetic breast reduction mammoplasty developed a dusky discoloration of the left nipple areolar complex, indicating imminent flap failure. The patient was immediately treated with topical nitroglycerin, oral pentoxifylline, and referred for HBO2. After her first HBO2 treatment, there was clinical improvement to the superior portion of the areolar flap, with little improvement inferiorly where the discoloration had remained essentially unchanged. To address this, we added leech therapy and discontinued the topical nitroglycerin. Ceftriaxone for Aeromonas prophylaxis was started, and leeches were attached two at a time and removed from the area once feeding had ceased. These were applied three times per day for three days while receiving HBO2 twice per day for six days. The patient's flap improved and completely healed by Week 8 without need for further surgery. This is the first case to our knowledge of successful breast flap salvage using a combination of leech therapy, HBO2, topical nitroglycerin and pentoxifylline.

Comparative Effectiveness of Pharmacological Interventions for Severe Alcoholic Hepatitis: A Systematic Review and Network Meta-analysis.

PubMed

Singh, Siddharth; Murad, Mohammad Hassan; Chandar, Apoorva K; Bongiorno, Connie M; Singal, Ashwani K; Atkinson, Stephen R; Thursz, Mark R; Loomba, Rohit; Shah, Vijay H

2015-10-01

Severe alcoholic hepatitis (AH) has high mortality. We assessed the comparative effectiveness of pharmacological interventions for severe AH, through a network meta-analysis combining direct and indirect treatment comparisons. We conducted a systematic literature review, through February 2015, for randomized controlled trials of adults with severe AH (discriminant function ≥32 and/or hepatic encephalopathy) that compared the efficacy of active pharmacologic interventions (corticosteroids, pentoxifylline, and N-acetylcysteine [NAC], alone or in combination) with each other or placebo, in reducing short-term mortality (primary outcome) and medium-term mortality, acute kidney injury, and/or infections (secondary outcomes). We performed direct and Bayesian network meta-analysis for all treatments, and used Grading of Recommendations Assessment, Development and Evaluation criteria to appraise quality of evidence. We included 22 randomized controlled trials (2621 patients) comparing 5 different interventions. In a direct meta-analysis, only corticosteroids decreased risk of short-term mortality. In a network meta-analysis, moderate quality evidence supported the use of corticosteroids alone (relative risk [RR], 0.54; 95% credible interval [CrI], 0.39-0.73) or in combination with pentoxifylline (RR, 0.53; 95% CrI, 0.36-0.78) or NAC (RR, 0.15; 95% CI, 0.05-0.39), to reduce short-term mortality; low quality evidence showed that pentoxifylline also decreased short-term mortality (RR, 0.70; 95% CrI, 0.50-0.97). The addition of NAC, but not pentoxifylline, to corticosteroids may be superior to corticosteroids alone for reducing short-term mortality. No treatment was effective in reducing medium-term mortality. Imprecise estimates and the small number of direct trials lowered the confidence in several comparisons. In patients with severe AH, pentoxifylline and corticosteroids (alone and in combination with pentoxifylline or NAC) can reduce short-term mortality. No treatment decreases risk of medium-term mortality. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Effect of pentoxifylline and vinpocetine on the healing of ischemic colon anastomosis: an experimental study.

PubMed

Sümer, Aziz; Altınlı, Ediz; Senger, Serkan; Köksal, Neşet; Onur, Ender; Eroğlu, Ersan; Güneş, Pembegül

2011-11-01

In the current study, we aimed to investigate the influences of pentoxifylline, which increases the flexibility, deformability and viscosity of the erythrocytes while reducing the aggregation abilities of the platelets, and vinpocetine, which has neuroprotective and antioxidant effects, on healing of colonic anastomoses. We used 30 Albino Wistar rats. Subjects were divided into three groups of 10 rats each. Colonic ischemia was established in all the groups. Following colonic transection, anastomosis was performed. Group A received intraperitoneal saline, whereas Group B and Group C received pentoxifylline and vinpocetine, respectively. The subjects were sacrificed on the postoperative 5th day by ether anesthesia, and their colonic bursting pressures were measured. The anastomotic area was excised for hydroxyproline assay and histopathologic examination. According to intergroup comparisons, colonic bursting pressure was found to be higher in the treatment groups than in the control group; however, the difference was not statistically significant. Intergroup comparisons regarding tissue hydroxyproline levels showed statistically significant differences between Groups A and B, Groups A and C and Groups B and C. Similar to pentoxifylline, vinpocetine was also shown to have a beneficial effect over ischemic colon anastomoses.

Evaluating the effects of pentoxifylline administration on experimental pressure sores in rats by biomechanical examinations

PubMed Central

Velaei, Kobra; Torkman, Giti; Rezaie, Fatemealsadat; Amini, Abdollah; Noruzian, Mohsen; Tavassol, Azaedh; Bayat, Mehernoush

2012-01-01

This study used a biomechanical test to evaluate the effects of pentoxifylline administration on the wound healing process of an experimental pressure sore induced in rats. Under general anesthesia and sterile conditions, experimental pressure sores generated by no. 25 Halsted mosquito forceps were inflicted on 12 adult male rats. Pentoxifylline was injected intraperitoneally at a dose of 50 mg/kg daily from the day the pressure sore was generated, for a period of 20 days. At the end of 20 days, rats were sacrificed and skin samples extracted. Samples were biomechanically examined by a material testing instrument for maximum stress (N mm2), work up to maximum force (N), and elastic stiffness (N/mm). In the experimental group, maximum stress (2.05±0.15) and work up to maximum force (N/mm) (63.75±4.97) were significantly higher than the control group (1.3±0.27 and 43.3±14.96, P=0.002 and P=0.035, respectively). Pentoxifylline administration significantly accelerated the wound healing process in experimental rats with pressure sores, compared to that of the control group. PMID:23091522

Evaluating the effects of pentoxifylline administration on experimental pressure sores in rats by biomechanical examinations.

PubMed

Velaei, Kobra; Bayat, Mohammad; Torkman, Giti; Rezaie, Fatemealsadat; Amini, Abdollah; Noruzian, Mohsen; Tavassol, Azaedh; Bayat, Mehernoush

2012-09-01

This study used a biomechanical test to evaluate the effects of pentoxifylline administration on the wound healing process of an experimental pressure sore induced in rats. Under general anesthesia and sterile conditions, experimental pressure sores generated by no. 25 Halsted mosquito forceps were inflicted on 12 adult male rats. Pentoxifylline was injected intraperitoneally at a dose of 50 mg/kg daily from the day the pressure sore was generated, for a period of 20 days. At the end of 20 days, rats were sacrificed and skin samples extracted. Samples were biomechanically examined by a material testing instrument for maximum stress (N mm(2)), work up to maximum force (N), and elastic stiffness (N/mm). In the experimental group, maximum stress (2.05±0.15) and work up to maximum force (N/mm) (63.75±4.97) were significantly higher than the control group (1.3±0.27 and 43.3±14.96, P=0.002 and P=0.035, respectively). Pentoxifylline administration significantly accelerated the wound healing process in experimental rats with pressure sores, compared to that of the control group.

Comparative clinical study between the effect of fenofibrate alone and its combination with pentoxifylline on biochemical parameters and liver stiffness in patients with non-alcoholic fatty liver disease.

PubMed

El-Haggar, Sahar Mohamed; Mostafa, Tarek Mohamed

2015-07-01

Non-alcoholic fatty liver disease is a common health problem associated with increased liver and vascular specific complications. The purpose of this study was to assess and compare the effect of fenofibrate alone or in combination with pentoxifylline on the measured biochemical parameters, inflammatory pathway and liver stiffness in patients with non-alcoholic fatty liver disease. The study design was randomized controlled trial. From July 2013 to June 2014, we recruited 90 non-alcoholic fatty liver patients from the Internal Medicine Department at Tanta University Hospital, Egypt. They were classified randomly into two groups to receive fenofibrate 300 mg daily or fenofibrate 300 mg daily plus pentoxifylline 1200 mg/day in three divided doses for 24 weeks. Fasting blood sample was obtained before and 24 weeks after treatment for biochemical analysis of liver and lipid panels, tumor necrosis factor-alpha, hyaluronic acid, transforming growth factor beta 1, fasting plasma insulin and fasting glucose. Liver stiffness measurement was carried out using fibro-scan. Data were statistically analyzed by paired and unpaired Student's t test. The data obtained suggests that adding pentoxifylline to fenofibrate does not provide a beneficial effect on lipid panel, but has a beneficial effect on indirect biochemical markers of hepatic fibrosis, a direct marker linked to matrix deposition (hyaluronic acid), a cytokine/growth factor linked to liver fibrosis (transforming growth factor beta 1), the inflammatory pathway, insulin resistance and liver stiffness as compared to fenofibrate alone. The combination pentoxifylline plus fenofibrate may represent a new therapeutic strategy for non-alcoholic fatty liver disease as it resulted in more beneficial effects on direct and indirect markers of liver fibrosis, liver stiffness, insulin resistance and inflammatory pathway implicated in NAFLD.

Oral Administration of Pentoxifylline Reduces Endometriosis-Like Lesions in a Nude Mouse Model.

PubMed

Perelló, Maria; González-Foruria, Iñaki; Castillo, Paola; Martínez-Florensa, Mario; Lozano, Francisco; Balasch, Juan; Carmona, Francisco

2017-06-01

Recent reports consider endometriosis to be an immunological disorder, thus suggesting potential efficacy of immunomodulators for its treatment. The aim of this study was to assess the effects of oral administration of pentoxifylline on endometriosis-like lesions in a heterologous mice model. Human endometrial tissue obtained from women (n = 5) undergoing surgery for benign conditions was implanted in nude female mice (n = 30). The animals were distributed into 3 experimental groups receiving: saline 0.1 mL/d (control, group 1); pentoxifylline 100 mg/kg/d (group 2), and pentoxifylline 200 mg/kg/d (group 3). After 28 days, the number of implants and the total volume of surgically extracted tissue were recorded. Immunohistochemical analysis was performed to assess the area of endometriosis and vascularization of endometriosis-like lesions. Cytokine levels in peritoneal fluid samples were measured. Macroscopic quantification showed a trend to dose-dependent reduction in the number of the endometriosis-like lesions after 28 days. The volume was significantly reduced in group 3 versus group 2 and controls (399.10 ± 120.68 mm 3 vs 276.75 ± 94.30 mm 3 and 145.33 ± 38.20 mm 3 , respectively; P = .04). Similarly, the mean area of endometriosis was significantly lower in group 3 (0.12 ± 0.08 mm 2 ) versus group 2 (1.35 ± 0.43 mm 2 ) and control (2.84 ± 0.60 mm 2 ; P = .001). Vascularization and cytokine levels were also reduced posttreatment. Our results suggest that the oral administration of pentoxifylline may be an alternative to current therapies for endometriosis. Nonetheless, further studies are required.

Role of pentoxifylline in non-alcoholic fatty liver disease in high-fat diet-induced obesity in mice.

PubMed

Acedo, Simone Coghetto; Caria, Cintia Rabelo E Paiva; Gotardo, Érica Martins Ferreira; Pereira, José Aires; Pedrazzoli, José; Ribeiro, Marcelo Lima; Gambero, Alessandra

2015-10-28

To study pentoxifylline effects in liver and adipose tissue inflammation in obese mice induced by high-fat diet (HFD). Male swiss mice (6-wk old) were fed a high-fat diet (HFD; 60% kcal from fat) or AIN-93 (control diet; 15% kcal from fat) for 12 wk and received pentoxifylline intraperitoneally (100 mg/kg per day) for the last 14 d. Glucose homeostasis was evaluated by measurements of basal glucose blood levels and insulin tolerance test two days before the end of the protocol. Final body weight was assessed. Epididymal adipose tissue was collected and weighted for adiposity evaluation. Liver and adipose tissue biopsies were homogenized in solubilization buffer and cytokines were measured in supernatant by enzyme immunoassay or multiplex kit, respectively. Hepatic histopathologic analyses were performed in sections of paraformaldehyde-fixed, paraffin-embedded liver specimens stained with hematoxylin-eosin by an independent pathologist. Steatosis (macrovesicular and microvesicular), ballooning degeneration and inflammation were histopathologically determined. Triglycerides measurements were performed after lipid extraction in liver tissue. Pentoxifylline treatment reduced microsteatosis and tumor necrosis factor (TNF)-α in liver (156.3 ± 17.2 and 62.6 ± 7.6 pg/mL of TNF-α for non-treated and treated obese mice, respectively; P < 0.05). Serum aspartate aminotransferase levels were also reduced (23.2 ± 6.9 and 12.1 ± 1.6 U/L for non-treated and treated obese mice, respectively; P < 0.05) but had no effect on glucose homeostasis. In obese adipose tissue, pentoxifylline reduced TNF-α (106.1 ± 17.6 and 51.1 ± 9.6 pg/mL for non-treated and treated obese mice, respectively; P < 0.05) and interleukin-6 (340.8 ± 51.3 and 166.6 ± 22.5 pg/mL for non-treated and treated obese mice, respectively; P < 0.05) levels; however, leptin (8.1 ± 0.7 and 23.1 ± 2.9 ng/mL for non-treated and treated lean mice, respectively; P < 0.05) and plasminogen activator inhibitor-1 (600.2 ± 32.3 and 1508.6 ± 210.4 pg/mL for non-treated and treated lean mice, respectively; P < 0.05) levels increased in lean adipose tissue. TNF-α level in the liver of lean mice also increased (29.6 ± 6.6 and 75.4 ± 12.6 pg/mL for non-treated and treated lean mice, respectively; P < 0.05) while triglycerides presented a tendency to reduction. Pentoxifylline was beneficial in obese mice improving liver and adipose tissue inflammation. Unexpectedly, pentoxifylline increased pro-inflammatory markers in the liver and adipose tissue of lean mice.

Role of pentoxifylline in non-alcoholic fatty liver disease in high-fat diet-induced obesity in mice

PubMed Central

Acedo, Simone Coghetto; Caria, Cintia Rabelo e Paiva; Gotardo, Érica Martins Ferreira; Pereira, José Aires; Pedrazzoli, José; Ribeiro, Marcelo Lima; Gambero, Alessandra

2015-01-01

AIM: To study pentoxifylline effects in liver and adipose tissue inflammation in obese mice induced by high-fat diet (HFD). METHODS: Male swiss mice (6-wk old) were fed a high-fat diet (HFD; 60% kcal from fat) or AIN-93 (control diet; 15% kcal from fat) for 12 wk and received pentoxifylline intraperitoneally (100 mg/kg per day) for the last 14 d. Glucose homeostasis was evaluated by measurements of basal glucose blood levels and insulin tolerance test two days before the end of the protocol. Final body weight was assessed. Epididymal adipose tissue was collected and weighted for adiposity evaluation. Liver and adipose tissue biopsies were homogenized in solubilization buffer and cytokines were measured in supernatant by enzyme immunoassay or multiplex kit, respectively. Hepatic histopathologic analyses were performed in sections of paraformaldehyde-fixed, paraffin-embedded liver specimens stained with hematoxylin-eosin by an independent pathologist. Steatosis (macrovesicular and microvesicular), ballooning degeneration and inflammation were histopathologically determined. Triglycerides measurements were performed after lipid extraction in liver tissue. RESULTS: Pentoxifylline treatment reduced microsteatosis and tumor necrosis factor (TNF)-α in liver (156.3 ± 17.2 and 62.6 ± 7.6 pg/mL of TNF-α for non-treated and treated obese mice, respectively; P < 0.05). Serum aspartate aminotransferase levels were also reduced (23.2 ± 6.9 and 12.1 ± 1.6 U/L for non-treated and treated obese mice, respectively; P < 0.05) but had no effect on glucose homeostasis. In obese adipose tissue, pentoxifylline reduced TNF-α (106.1 ± 17.6 and 51.1 ± 9.6 pg/mL for non-treated and treated obese mice, respectively; P < 0.05) and interleukin-6 (340.8 ± 51.3 and 166.6 ± 22.5 pg/mL for non-treated and treated obese mice, respectively; P < 0.05) levels; however, leptin (8.1 ± 0.7 and 23.1 ± 2.9 ng/mL for non-treated and treated lean mice, respectively; P < 0.05) and plasminogen activator inhibitor-1 (600.2 ± 32.3 and 1508.6 ± 210.4 pg/mL for non-treated and treated lean mice, respectively; P < 0.05) levels increased in lean adipose tissue. TNF-α level in the liver of lean mice also increased (29.6 ± 6.6 and 75.4 ± 12.6 pg/mL for non-treated and treated lean mice, respectively; P < 0.05) while triglycerides presented a tendency to reduction. CONCLUSION: Pentoxifylline was beneficial in obese mice improving liver and adipose tissue inflammation. Unexpectedly, pentoxifylline increased pro-inflammatory markers in the liver and adipose tissue of lean mice. PMID:26523207

[The effect of antiinflammatory therapy with dexamethasone and dexamethasone with pentoxifylline on the course of bacterial meningitis].

PubMed

Bociaga-Jasik, Monika; Kalinowska-Nowak, Anna; Garlicki, Aleksander; Mach, Tomasz

2003-01-01

Despite of antimicrobial therapy mortality rate in the bacterial meningitis (BM) is high. The aim of the study was to assess the influence of anti-inflammatory treatment with dexamethasone and dexamethasone with pentoxifylline on the course of this disease and concentration of proinflammatory cytokines TNF-alpha, IL-1 beta, II-8 in the cerebrospinal fluid (CSF). 42 patients with the BM were analysed. They were divided into three groups on the basis of applied therapy: A--treated only with antibiotics, A+D--treated with antibiotics and dexamethasone, A+D+P--treated with antibiotics, dexamethasone and pentoxifylline. Anti-inflammatory therapy did not have impact on the resolution of inflammation (pleocytosis, protein and glucose level) in the CSF. However, it was established that adjuvant treatment with dexa-methasone and pentoxifylline has beneficial effect on the course of the BM. In this group 61.5% of patients recovered, in comparison with 28.6% in the group A+D and 26.7% in the group A. Mortality rate was: in the group A--33%, A+D--21.4%, A+D+P--7.7% (p = 0.01). Correlation between the outcome of the BM in the investigated groups and cytokines concentration in CSF was observed. In the group A+D+P all patients responded to the therapy with decrease of cytokine concentration, and coefficients of variation were low (TNF-alpha--1%, IL-1 beta--23.6%, IL-8--18.9%). Also in the group A+D decrease of cytokines concentration in the CSF was observed, however was not such significant in all cases. In the group of patients treated only with antibiotics concentration of cytokines in the CSF varied, even increased in some of them. Our investigation indicates that inhibition of cytokines production in central nervous system (CNS) with dexamethasone and pentoxifylline improves the outcome of BM and is associated with the reduction of neurological sequels and deaths.

Hypothesis: Pentoxifylline explores new horizons in treatment of preeclampsia.

PubMed

Azimi, Arsalan; Ziaee, Seyyed Mohyeddin; Farhadi, Pouya; Sagheb, Mohammad Mahdi

2015-10-01

Preeclampsia, the leading cause of maternal morbidity and perinatal mortality, initiates as inappropriate immune response to trophoblastic invasion impairs placentation and placental circulation. A poorly perfused placenta generates superoxide anions as well as anti-angiogenic factors and this series of events result in impairment of endothelial function, followed by maternal morbidities such as hypertension, kidney injury and proteinuria. Renal loss of anti-coagulant proteins and subsequent hyper-coagulable state along with endothelial dysfunction accelerates progression of the disease toward eclampsia. Since Pentoxifylline, a methyl-xanthine derivative known for enhancement of vascular endothelial function, down-regulation of many inflammatory cytokines increased during preeclampsia, improvement of placental circulation, reduction of ischemia-reperfusion injury, enhancement of vasodilatation and endothelial function, ameliorating proteinuria, inhibition of platelet aggregation and decreasing risk of preterm labor, which are all amongst morbidities of preeclampsia, here it is hypothesized that Pentoxifylline prevents development of preeclampsia and/or decelerate progression of the disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

Corticosteroids, nutrition, pentoxifylline, or fecal microbiota transplantation for severe alcoholic hepatitis.

PubMed

Philips, Cyriac Abby; Phadke, Nikhil; Ganesan, Karthik; Ranade, Shatakshi; Augustine, Philip

2018-06-21

Alcohol-induced intestinal dysbiosis is central to the development of the severe alcoholic liver disease. We present the first study to compare outcomes in patients of severe alcoholic hepatitis (SAH) on nutritional therapy, corticosteroids, pentoxifylline, and healthy donor fecal transplantation (FMT) and discuss distinct microbial community and microbiome metabolic functional changes after FMT. Out of 1271 liver disease patients, 809 (63.7%) were diagnosed to have the alcoholic liver disease, of which 51 patients (8 treated with corticosteroids, 17 with nutritional support only, 10 with pentoxifylline, 16 receiving FMT) were included. Clinical, biochemical parameters, liver disease, and alcoholic hepatitis severity scores at baseline and mortality at the end of 1 and 3 months were analyzed between groups. Stool microbiota (SM) analysis was performed for healthy controls (HC) and respective recipients after FMT. All the patients were male. The proportions of patients surviving at the end of 1 and 3 months in the steroids, nutrition, pentoxifylline, and FMT group were 63%, 47%, 40% and 75% [p = 0.179] and 38%, 29%, 30%, and 75% [p = 0.036], respectively. When compared with FMT, relative risk and hazard ratios for death were higher in all the other groups. Following FMT, distinct and beneficial modulation of SM and pathways of dysregulated metabolism, infections, inflammation, and oxidative stress in SAH patients were noted in tandem with improved clinical outcomes. Healthy donor FMT for SAH improves survival beyond what is offered by current therapies and can function as a cost-effective bridge to liver transplant (LT) or for improving transplant-free survival. Larger studies and randomized trials are unmet needs.

The Medical Treatment of New-Onset Peripartum Cardiomyopathy: A Systematic Review of Prospective Studies.

PubMed

Desplantie, Olivier; Tremblay-Gravel, Maxime; Avram, Robert; Marquis-Gravel, Guillaume; Ducharme, Anique; Jolicoeur, E Marc

2015-12-01

Peripartum cardiomyopathy (PPCM) is a rare disorder with potentially fatal consequences, which occurs mainly in previously healthy women. The aetiology of PPCM remains unknown and various pathologic mechanisms have been proposed, including immune-mediated injuries and impaired response to oxidative stress and inflammatory cytokines. Several therapies have been studied, but few have been validated in a well-designed randomized controlled trial. In the present study we sought to review the medical treatment intended for acute PPCM. To this end, we performed a systematic review of the literature of randomized and nonrandomized prospective clinical studies. We identified 2 randomized controlled trials that evaluated the dopamine agonist bromocriptine and the inotrope levosimendan, respectively, and 1 nonrandomized study that evaluated the nonselective phosphodiesterase inhibitor pentoxifylline. We reviewed the pathophysiological, pharmacological, and clinical properties for each treatment option identified. Bromocriptine and pentoxifylline both improved left ventricular systolic function and patient-oriented clinical end points and levosimendan did not improve mortality or echocardiographic findings of PPCM. In this review we identified bromocriptine and pentoxifylline, but not levosimendan, as potentially useful agents to improve left ventricle function and outcomes in PPCM. Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

[Role of functional state of neuronal mitochondria of cerebral cortex in mechanisms of nootropic activity of neuroprotectors in rats with alloxan hyperglycemia].

PubMed

Zhiliuk, V I; Mamchur, V I; Pavlov, S V

2015-01-01

The influence of citicoline, phenylpiracetam, pentoxifylline and N-phenylacetyl-L-prolylglycine on cognitive processes and functional state of mitochondria in the neocortex of alloxan-diabetic rats has been studied. The drug effects on cognitive processes were assessed using passive avoidance tests in the dark-light camera. Latent period and the number of animals with amnesia skill on 6th and 20th days of drug administration were recorded. Functional status of mitochondria was assessed by mitochondrial pore opening and mitochondrial transmembrane potential (Y) on 20th day. It has been established that course administration of phenylpiracetam, citicoline and to a lesser extent N-phenylacetyl-L-prolylglycine, but not pentoxifylline, improves the processes of learning and storing conditional skill. At the same time, the nootropic activity of studied drugs was comparable to their effect on the functional state of mitochondria in neocortical neurons in rats with chronic hyperglycemia. According to mitoprotective activity (prevention of opening of mitochondrial cyclosporin-A-sensitive pores and restoration of mitochondrial transmembrane potential), the maximum potential was observed for citicoline and phenylpiracetam, and the minimum--for pentoxifylline. The results point out the importance of mitoprotective properties in nootropic effects of studied drugs.

[Evaluation of treatment outcome after nicergoline and pentoxifylline in patients with ischemic stroke].

PubMed

Brola, W

1997-01-01

The study has been taken up to compare the effect of treatment with nicergoline or pentoxifylline and typical treatment in early ischaemic stroke. The study included 121 patients aged 42-75, with the ischaemic stroke confirmed by CT scan, in early stage of stroke (within 24 hours after onset). Excluded from the study were patients with severe physical diseases. The patients were divided into three groups. Group I was treated typically, group II was given both typical treatment and nicergoline during 30 days, with a daily dose 8 mg i.v. within the first 5 days followed by an oral delivery with a dose of 30 mg per day during the following 25 days. Group III had been profited from a typical, appropriate therapy and pentoxifylline delivery during 30 days as well, with a daily dose of 1200 mg i.v. within the first 5 days followed by an oral dose of 800 mg subsequent days. The neurological state was assessed according to the European Stroke Scale (ESS), general fitness according to the Karnofsky Scale (KS) at the admission and after 30 days of the treatment. After 30 days of the treatment, no statistically essential differences between all study groups was found in: 1) mortality, 2) mean survival time, 3) neurological state, 4) patients general fitness. According to the above results the beneficial influence of nicergoline and pentoxiphylline treatment of ischaemic stroke was not confirmed.

Pentoxifylline Treatment in Acute Pancreatitis (AP)

ClinicalTrials.gov

2018-02-21

Acute Pancreatitis (AP); Gallstone Pancreatitis; Alcoholic Pancreatitis; Post-ERCP/Post-procedural Pancreatitis; Trauma Acute Pancreatitis; Hypertriglyceridemia Acute Pancreatitis; Idiopathic (Unknown) Acute Pancreatitis; Medication Induced Acute Pancreatitis; Cancer Acute Pancreatitis; Miscellaneous (i.e. Acute on Chronic Pancreatitis)

Kinetic activity, membrane mitochondrial potential, lipid peroxidation, intracellular pH and calcium of frozen/thawed bovine spermatozoa treated with metabolic enhancers.

PubMed

Boni, R; Gallo, A; Cecchini, S

2017-01-01

Owing to the progressive decline of sperm motility during storage there is a need to find substances capable of enhancing sperm energy metabolism and motility and/or preserving it from oxidative damage. The aim of this study was to evaluate in frozen/thawed bovine spermatozoa the effect of several compounds, such as myo-inositol, pentoxifylline, penicillamine + hypotaurine + epinephrine mixture (PHE), caffeine and coenzyme Q10+ zinc + d-aspartate mixture (CZA), on either kinetic or metabolic parameters. Sperm kinetics was evaluated by Sperm Class Analyser whereas specific fluorochromes were used to evaluated mitochondrial membrane potential (MMP), intracellular pH, intracellular calcium concentration and lipid peroxidation. Lipid peroxidation was also evaluated by TBARS analysis. Treatments significantly affected total and progressive motility with different dynamics in relation to the incubation time. After the first hour of incubation, CZA treatment produced the best performance in total and progressive sperm motility as well as in curvilinear velocity, average path velocity and amplitude of head displacement, whereas pentoxifylline stimulated the highest straight-line velocity. MMP showed higher values (p < 0.01) after treatment with pentoxifylline and PHE. Intracytoplasmic calcium concentration and lipid peroxidation were significantly (p < 0.05) affected by the incubation time rather than the treatments. Intracellular pH varied significantly (p < 0.01) in relation to either the incubation time or treatments. In particular, it showed a progressive increase throughout incubation with values in control group significantly higher than in myo-inositol, PHE, caffeine, pentoxifylline and CZA groups (7.37 ± 0.03 vs. 7.29 ± 0.03, 7.28 ± 0.03, 7.26 ± 0.03, 7.22 ± 0.03 and 7.00 ± 0.03, respectively; p < 0.01).; however, among treatments, CZA displayed the lowest values. Significant correlations were found between sperm kinetic and metabolic parameters. These findings provide new comparative information on the effects of putative metabolic enhancers on kinetics and metabolic activities of bovine spermatozoa. In this study, a rapid methodological approach for evaluating sperm quality is proposed. © 2016 American Society of Andrology and European Academy of Andrology.

Disruption of p53 function sensitizes breast cancer MCF-7 cells to cisplatin and pentoxifylline.

PubMed

Fan, S; Smith, M L; Rivet, D J; Duba, D; Zhan, Q; Kohn, K W; Fornace, A J; O'Connor, P M

1995-04-15

The possibility that appropriately designed chemotherapy could act selectively against p53-defective tumor cells was explored in MCF-7 human breast cancer cells. These cells were chosen because they have normal p53 function but are representative of a tumor cell type that does not readily undergo p53-dependent apoptosis. Two sublines (MCF-7/E6 and MCF-7/mu-p53) were established in which p53 function was disrupted by transfection with either the human papillomavirus type-16 E6 gene or a dominant-negative mutant p53 gene. p53 function in MCF-7/E6 and MCF-7/mu-p53 cells was defective relative to control cells in that there were no increases in p53 or p21Waf1/Cip1 protein levels and no G1 arrest following exposure to ionizing radiation. Survival assays showed that p53 disruption sensitized MCF-7 cells to cisplatin (CDDP) but not to several other DNA-damaging agents. CDDP sensitization was not limited to MCF-7 cells since p53 disruption in human colon carcinoma RKO cells also enhanced sensitivity to CDDP. Contrary to the other DNA-damaging agents tested, CDDP-induced DNA lesions are repaired extensively by nucleotide excision, and in agreement with a defect in this process, MCF-7/E6 and MCF-7/mu-p53 cells exhibited a reduced ability to repair a CDDP-damaged chloramphenicol acetyltransferase-reporter plasmid transfected into the cells. Therefore, we attributed the increased CDDP sensitivity of MCF-7 cells with disrupted p53 to defects in G1 checkpoint control, nucleotide excision repair, or both. The G2 checkpoint inhibitor pentoxifylline exhibited synergism with CDDP in killing MCF-7/E6 cells but did not affect sensitivity of the control cells. Moreover, pentoxifylline inhibited G2 checkpoint function to a greater extent in MCF-7/E6 than in the parental cells. These results suggested that, in the absence of p53 function, cancer cells are more vulnerable to G2 checkpoint abrogators. Our results show that a combination of CDDP and pentoxifylline is capable of synergistic and preferential killing of p53-defective tumor cells that do not readily undergo apoptosis.

The effect of pentoxifylline on spontaneous and experimental metastasis of the mouse Neuro2a neuroblastoma.

PubMed

Amirkhosravi, A; Warnes, G; Biggerstaff, J; Malik, Z; May, K; Francis, J L

1997-07-01

Pentoxifylline (PTX) has been reported to have both direct and indirect anti-tumor effects in experimental tumor models. We studied the effect of PTX on (1) the proliferation of Neuro2a mouse neuroblastoma cells in vitro and in vivo, (2) spontaneous and experimental metastasis, (3) tumor cell membrane fluidity and (4) adhesion to a fibronectin-coated surface. PTX significantly reduced the proliferation of Neuro2a cells in vitro as determined by DNA measurement (P < 0.01) and total cell count (P < 0.02). In vivo, PTX reduced the growth of subcutaneously transplanted primary tumors in syngeneic A/J mice (P < 0.01; n = 15). All seven animals (100%) receiving intravenous tumor cells developed extensive liver metastasis. In contrast, only 1/11 (9%) of animals pre-treated with oral PTX and injected with PTX-treated cells developed liver metastases. Of five mice receiving PTX-treated cells without oral pretreatment of PTX, two out of five (40%) developed liver metastases. There was a slight, but not significant (P = 0.08) increase in both experimental and spontaneous lung metastases formation in PTX-treated animals. However, tumor nodule formation on the lung surface was inefficient. PTX also increased membrane fluidity of the Neuro2a cells and significantly decreased tumor cell adhesion to fibronectin-coated microtiter wells (P < 0.01). We conclude that PTX has a cytostatic effect on the Neuro2a mouse neuroblastoma and exerts an anti-tumor effect on liver metastases following intravenous administration of neuroblastoma cells. Whether these results are directly related to the changes in membrane properties caused by pentoxifylline remains to be established.

The protective effect of pentoxifylline versus silymarin on the pancreas through increasing adenosine by CD39 in a rat model of liver cirrhosis: Pharmacological, biochemical and histological study.

PubMed

Mohamed, Doaa I; Nabih, Enas S; El-Waseef, Dalia A A; El-Kharashi, Omnyah A; Abd El Samad, Abeer A

2018-04-20

Impaired glucose homoeostasis due to insulin resistance and decrease sensitivity of pancreatic β-cells is a feature of liver disease and results into hepatogenous diabetes. Decrease expression of CD39 was linked to inflammation and occurrence of diabetes. Therefore, we performed this study to explore the protective effect of pentoxifylline (PTX) and silymarin administration on the β-cells of the pancreas in a rat model of thioacetamide induced liver cirrhosis. Biochemical, histological and immunohistochemistry studies of the liver and pancreas were performed and provided an evidence on the protective effect of PTX to pancreatic β-cells compared to silymarin. Also, silymarin induced a significant improvement of liver cirrhosis compared to PTX. In conclusion, the potential protective effect of PTX against β-cells deterioration could be attributed to increasing pancreatic CD39 expression and the subsequent increase of adenosine. Copyright © 2018 Elsevier B.V. All rights reserved.

IgG1 antimycobacterial antibodies can reverse the inhibitory effect of pentoxifylline on tumour necrosis factor alpha (TNF-alpha) secreted by mycobacterial antigen-stimulated adherent cells.

PubMed

Thakurdas, S M; Hasan, Z; Hussain, R

2004-05-01

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)-alpha. Mycobacterial components directly stimulate adherent cells to secrete TNF-alpha. We have shown recently that IgG1 antimycobacterial antibodies play a role in augmenting TNF-alpha in purified protein derivative (PPD)-stimulated adherent cells from non-BCG-vaccinated donors. We now show that IgG1 antibodies can also augment TNF-alpha 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-alpha 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.

Red blood cell aggregation changes are depended on its initial value: Effect of long-term drug treatment and short-term cell incubation with drug.

PubMed

Muravyov, A V; Tikhomirova, I A; Maimistova, A A; Bulaeva, S V; Mikhailov, P V; Kislov, N V

2011-01-01

This study was designed to investigate whether the red cell aggregation depends on its initial level under drug therapy or cell incubation with bioactive chemical compounds. Sixty six subjects were enrolled onto this study, and sub-divided into two groups: the first group of patients (n = 36) with cerebral atherosclerosis received pentoxifylline therapy (400 mg, thrice daily) for 4 weeks. The patients of the second group were initially treated with Epoetin beta 10,000 units subcutaneously thrice a week, for 4 weeks. The second group - adult anemic patients (n = 30) with the confirmed diagnosis of solid cancer (Hb < 100 g/L). After 4 weeks of pentoxifylline treatment the red cell aggregation increased (p < 0.05) in the patients with initially low RBCA. On the other hand in the patients with initially high RBCA treatment with pentoxifylline reduced it markedly (p < 0.01). In vitro experiments with pentoxifylline RBC incubation resulted in a decrease of the initially high RBCA by 47% (p < 0.01), whereas in the sub-group with initially low RBCA it increased. It was observed that after 4 weeks of epoetin-beta treatment 75% the anemic patients with initially high RBCA had an aggregation lowering. The drop of aggregation was about 34% (p < 0.01). At the same time 25% of the study patients had a significant RBCA increase (p < 0.05) after treatment. The initially low red cell aggregation after incubation with epoetin-beta was markedly increased by 122% (p < 0.05). On the contrary initially high RBCA was reduced by 47% (p < 0.05). When forskolin (10 μM) was added to the RBC suspensions the RBCA was increased in sub-group of subjects with initially low aggregation and it was decreased in sub-group with initially high one. The similar RBCA changes were observed when RBC suspensions were incubated with vinpocetine, calcium ionophore (A23187), Phorbol 12-myristate 13-acetate (PMA) as a protein kinase C (PKC) stimulator. A major finding of this study is that the red cell aggregation effects of some drugs depend markedly on the initial, pre-treatment aggregation status of the patients. These results demonstrate that the different red blood cell aggregation responses to the biological stimuli depend strongly on the initial, pre-treatment status of the subject and the most probably it is connected with the crosstalk between the adenylyl cyclase signaling pathway and Ca2+ regulatory mechanism.

In Vivo T Cell Signaling Leading to Apoptosis vs. Cytokine Production

DTIC Science & Technology

1995-08-17

the endothelium ( Bergese et a/.. 1994~ Webb and Sprent.1993). H-2 alloreactive T cells home to the gut-associated lymphoid tissues with a significant...receptor release in mice; effects of pentoxifylline, methylprednisolone.. anti- TNF, and anti-IFN-y. Journal of Immunology 153.. 499-506. Bergese

Randomized Trial of Pentoxifylline and Vitamin E vs Standard Follow-up After Breast Irradiation to Prevent Breast Fibrosis, Evaluated by Tissue Compliance Meter

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jacobson, Geraldine, E-mail: geraldine-jacobson@uiowa.edu; Bhatia, Sudershan; Smith, Brian J.

Purpose: To conduct a randomized clinical trial to determine whether the combination of pentoxifylline (PTX) and vitamin E given for 6 months after breast/chest wall irradiation effectively prevents radiation-induced fibrosis (RIF). Methods and Materials: Fifty-three breast cancer patients with localized disease were enrolled and randomized to treatment with oral PTX 400 mg 3 times daily and oral vitamin E 400 IU daily for 6 months after radiation (n=26), or standard follow up (n=27). Tissue compliance meter (TCM) measurements were obtained at 18 months to compare tissue compliance in the irradiated and untreated breast/chest wall in treated subjects and controls. Measurementsmore » were obtained at 2 mirror image sites on each breast/chest wall, and the average difference in tissue compliance was scored. Differences in TCM measurements were compared using a t test. Subjects were followed a minimum of 2 years for local recurrence, disease-free survival, and overall survival. Results: The mean difference in TCM measurements in the 2 groups was 0.88 mm, median of 1.00 mm (treated) and 2.10 mm, median of 2.4 mm (untreated). The difference between the 2 groups was significant (P=.0478). Overall survival (100% treated, 90.6% controls at 5 years) and disease-free survival (96.2% treated, 86.8% controls at 5 years) were not significantly different in the 2 groups. Conclusions: This study of postirradiation breast cancer patients treated with PTX/vitamin E or standard follow-up indicated a significant difference in radiation-induced fibrosis as measured by TCM. There was no observed impact on local control or survival within the first 2 years of follow-up. The treatment was safe and well tolerated. Pentoxifylline/vitamin E may be clinically useful in preventing fibrosis after radiation in high-risk patients.« less

Effect of TNF-α production inhibitors on the production of pro-inflammatory cytokines by peripheral blood mononuclear cells from HTLV-1-infected individuals.

PubMed

Luna, T; Santos, S B; Nascimento, M; Porto, M A F; Muniz, A L; Carvalho, E M; Jesus, A R

2011-11-01

Human T lymphotropic virus type 1 (HTLV-1) is the causal agent of myelopathy/tropical spastic paraparesis (HAM/TSP), a disease mediated by the immune response. HTLV-1 induces a spontaneous proliferation and production of pro-inflammatory cytokines by T cells, and increasing interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) levels are potentially involved in tissue damage in diseases related to HTLV-1. This exaggerated immune response is also due to an inability of the natural regulatory mechanisms to down-modulate the immune response in this group of patients. TNF-α inhibitors reduce inflammation and have been shown to improve chronic inflammatory diseases in clinical trials. The aim of this study was to evaluate the ability of pentoxifylline, forskolin, rolipram, and thalidomide to decrease in vitro production of TNF-α and IFN-γ in cells of HTLV-1-infected subjects. Participants of the study included 19 patients with HAM/TSP (mean age, 53 ± 11; male:female ratio, 1:1) and 18 HTLV-1 carriers (mean age, 47 ± 11; male:female ratio, 1:2.6). Cytokines were determined by ELISA in supernatants of mononuclear cell cultures. Pentoxifylline inhibited TNF-α and IFN-γ synthesis with the minimum dose used (50 µM). The results with forskolin were similar to those observed with pentoxifylline. The doses of rolipram used were 0.01-1 µM and the best inhibition of TNF-α production was achieved with 1 µM and for IFN-γ production it was 0.01 µM. The minimum dose of thalidomide used (1 µM) inhibited TNF-α production but thalidomide did not inhibit IFN-γ production even when the maximum dose (50 µM) was used. All drugs had an in vitro inhibitory effect on TNF-α production and, with the exception of thalidomide, all of them also decreased IFN-γ production.

Bicarbonate is required for migration of sperm epididymal protein DE (CRISP-1) to the equatorial segment and expression of rat sperm fusion ability.

PubMed

Da Ros, Vanina G; Munuce, María J; Cohen, Débora J; Marín-Briggiler, Clara I; Busso, Dolores; Visconti, Pablo E; Cuasnicú, Patricia S

2004-05-01

Numerous studies have demonstrated that sperm capacitation is a bicarbonate-dependent process. In the rat, capacitation has not been studied as much as in other species, mainly because of the difficulties in carrying out functional assays with this animal model. In the present study, we have examined the influence of bicarbonate in the overall rat sperm capacitation process by analyzing involvement of the anion in 1) protein tyrosine phosphorylation, 2) migration of epididymal protein DE (also known as CRISP-1) from the dorsal region to the equatorial segment of the sperm head that occurs during capacitation, and 3) ability of sperm to fuse with the egg. Incubation of sperm under capacitating conditions produced a time-dependent increase in protein tyrosine phosphorylation. This phosphorylation did not occur in the absence of HCO3- and rapidly increased by either exposure of sperm to HCO3- or replacement of the anion by a cAMP analog (dibutyryl-cAMP) and a phosphodiesterase inhibitor (pentoxifylline). The absence of HCO3- also produced a significant decrease in the percentage of cells showing migration of DE to the equatorial segment. This parameter was completely restored by addition of the anion, but dibutyryl-cAMP and pentoxifylline were not sufficient to overcome the decrease in DE migration. Sperm capacitated in the absence of HCO3- were unable to penetrate zona-free eggs independent of the presence of the anion during gamete coincubation. Exposure of these sperm to bicarbonate, or replacement of the anion by dibutyryl-cAMP and pentoxifylline, only partially restored the sperm fusion ability. Altogether, these results indicate that, in addition to its influence on protein tyrosine phosphorylation, bicarbonate is required to support other rat sperm capacitation- associated events, such as migration of DE to the equatorial segment, and expression of the ability of sperm to fuse with the egg.

Pentoxifylline for Anemia in Chronic Kidney Disease: A Systematic Review and Meta-Analysis

PubMed Central

Bolignano, Davide; D’Arrigo, Graziella; Pisano, Anna; Coppolino, Giuseppe

2015-01-01

Background Pentoxifylline (PTX) is a promising therapeutic approach for reducing inflammation and improving anemia associated to various systemic disorders. However, whether this agent may be helpful for anemia management also in CKD patients is still object of debate. Study Design Systematic review and meta-analysis. Population Adults with CKD (any KDOQI stage, including ESKD patients on regular dialysis) and anemia (Hb<13 g/dL in men or < 12 g/dL in women). Search Strategy and Sources Cochrane CENTRAL, EMBASE, Ovid-MEDLINE and PubMed were searched for studies providing data on the effects of PTX on anemia parameters in CKD patients without design or follow-up restriction. Intervention PTX derivatives at any dose regimen. Outcomes Hemoglobin, hematocrit, ESAs dosage and resistance (ERI), iron indexes (ferritin, serum iron, TIBC, transferrin and serum hepcidin) and adverse events. Results We retrieved 11 studies (377 patients) including seven randomized controlled trials (all comparing PTX to placebo or standard therapy) one retrospective case-control study and three prospective uncontrolled studies. Overall, PTX increased hemoglobin in three uncontrolled studies but such improvement was not confirmed in a meta-analysis of seven studies (299 patients) (MD 0.12 g/dL, 95% CI -0.22 to 0.47). Similarly, there were no conclusive effects of PTX on hematocrit, ESAs dose, ferritin and TSAT in pooled analyses. Data on serum iron, ERI, TIBC and hepcidin were based on single studies. No evidence of increased rate of adverse events was also noticed. Limitations Small sample size and limited number of studies. High heterogeneity among studies with respect to CKD and anemia severity, duration of intervention and responsiveness/current therapy with iron or ESAs. Conclusions There is currently no conclusive evidence supporting the utility of pentoxifylline for improving anemia control in CKD patients. Future trials designed on hard, patient-centered outcomes with larger sample size and longer follow-up are advocated. PMID:26237421

Inhalation Injury.

DTIC Science & Technology

1994-01-01

spontaneously or assisted ), ᝺% since the elimination half-life supplemental 100% oxygen should be (t1, 2 ) for COHb is dependent on oxygen...persistent apy point out the increased incidence of hypovolemic shock and renal failure. fires involving polyurethanes, which Chest physiotherapy to...FITZPATRICK AND W. G. CIOFFI, JR. icals, the role of deficient surfactant Also in an animal study, pentoxifylline function, prevention of tracheobron- has been

Review of drug treatment of oral submucous fibrosis.

PubMed

Chole, Revant H; Gondivkar, Shailesh M; Gadbail, Amol R; Balsaraf, Swati; Chaudhary, Sudesh; Dhore, Snehal V; Ghonmode, Sumeet; Balwani, Satish; Mankar, Mugdha; Tiwari, Manish; Parikh, Rima V

2012-05-01

This study undertook a review of the literature on drug treatment of oral submucous fibrosis. An electronic search was carried out for articles published between January 1960 to November 2011. Studies with high level of evidence were included. The levels of evidence of the articles were classified after the guidelines of the Oxford Centre for Evidence-Based Medicine. The main outcome measures used were improvement in oral ulceration, burning sensation, blanching and trismus. Only 13 publications showed a high level of evidence (3 randomized controlled trials and 10 clinical trials/controlled clinical trials), with a total of 1157 patients. Drugs like steroids, hyaluronidase, human placenta extracts, chymotrypsin and collagenase, pentoxifylline, nylidrin hydrochloride, iron and multivitamin supplements including lycopene, have been used. Only systemic agents were associated with few adverse effects like gastritis, gastric irritation and peripheral flushing with pentoxifylline, and flushingly warm skin with nylidrin hydrochloride; all other side-effects were mild and mainly local. Few studies with high levels of evidence were found. The drug treatment that is currently available for oral submucous fibrosis is clearly inadequate. There is a need for high-quality randomized controlled trials with carefully selected and standardized outcome measures. Copyright © 2011 Elsevier Ltd. All rights reserved.

Venous ulcer review

PubMed Central

Bevis, Paul; Earnshaw, Jonothan

2011-01-01

Clinical question: What is the best treatment for venous ulcers? Results: Compression aids ulcer healing. Pentoxifylline can aid ulcer healing. Artificial skin grafts are more effective than other skin grafts in helping ulcer healing. Correction of underlying venous incompetence reduces ulcer recurrence. Implementation: Potential pitfalls to avoid are: Failure to exclude underlying arterial disease before application of compression.Unusual-looking ulcers or those slow to heal should be biopsied to exclude malignant transformation. PMID:21673869

Alcoholic steatohepatitis (ASH) and alcoholic hepatitis (AH): cascade of events, clinical aspects, and pharmacotherapy options.

PubMed

Teschke, Rolf

2018-06-01

Clinicians caring for patients with alcoholic hepatitis (AH) are often confronted with the question of the best pharmacotherapy to be used. Areas covered: This article covers metabolic aspects of alcohol as the basis of understanding pharmacotherapy and to facilitate choosing the drug therapeutic options for patients with severe AH. Expert opinion: Alcoholic steatohepatitis (ASH) and alcoholic hepatitis (AH) as terms are often used interchangeably in scientific literature but a stringent differentiation is recommended for proper clarity. As opposed to ASH, the clinical course of AH is often severe and requires an effective drug treatment strategy, in addition to absolute alcohol abstinence and nutritional support. Drug options include corticosteroids as a first choice and pentoxifylline, an inhibitor of phosphodiesterase, as a second line therapy, especially in patients with contraindications for a corticosteroid therapy such as infections or sepsis. At seven days under corticosteroids, treatment should be terminated in non-responders, and patients must then be evaluated for liver transplantation. Pentoxifylline is not effective as a rescue therapy for these patients. Other treatments such as infliximab, propylthiouracil, N-acetylcysteine, silymarin, colchicine, insulin and glucagon, oxandrolone, testosterone, and polyunsaturated lecithin are not effective in severe AH. For liver transplantation, few patients will be eligible.

Investigation into the role of phosphodiesterase IV in bronchorelaxation, including studies with human bronchus.

PubMed Central

Cortijo, J.; Bou, J.; Beleta, J.; Cardelús, I.; Llenas, J.; Morcillo, E.; Gristwood, R. W.

1993-01-01

1. We have investigated the role of cyclic nucleotide phosphodiesterase IV (PDE IV) in the relaxation of human bronchus and guinea-pig trachea in vitro and in guinea-pigs in vivo. 2. Functional studies showed that the selective PDE IV inhibitors, rolipram and denbufylline, relaxed human and guinea-pig preparations in vitro. 3. Two clinically used xanthine non-selective PDE inhibitors, theophylline and pentoxifylline, were also effective in these preparations, but were much less potent than the selective agents used. 4. The rank order of potency for the four PDE inhibitors in both species was similar. 5. Biochemical studies indicated that PDE IV was the major PDE isoform present in the human bronchial tissue. PDEs I, II and V were also identified. 6. Theophylline and pentoxifylline were, as expected, non-selective inhibitors of the human enzymes, but there was a good correlation between PDE IV inhibitory and bronchorelaxation potencies, suggesting that PDE IV inhibition is important for the clinical bronchodilator activities of the two xanthine compounds. 7. We have confirmed the ability of selective PDE IV inhibitors to cause bronchodilatation in guinea-pigs in vivo. 8. We conclude that our study has provided further evidence that selective PDE IV inhibitors could act as bronchodilators in the clinic. PMID:8383567

Pentoxifylline during steroid window phase at induction to remission increases apoptosis in childhood with acute lymphoblastic leukemia.

PubMed

Gonzalez-Ramella, O; Ortiz-Lazareno, P C; Jiménez-López, X; Gallegos-Castorena, S; Hernández-Flores, G; Medina-Barajas, F; Meza-Arroyo, J; Jave-Suárez, L F; Lerma-Díaz, J M; Sánchez-Zubieta, F; Bravo-Cuellar, A

2016-04-01

Pentoxifylline (PTX) has been shown to increase chemotherapy-induced apoptosis. A clinical trial was developed to evaluate the effect of the addition of PTX to the induction steroid window phase in children with acute lymphoblastic leukemia (ALL). Thirty-two children were enrolled on this study. Children with a new diagnosis of ALL were randomly assigned to receive prednisone (PRD) 40 mg/m(2)/day only during the 7-day treatment pre-phase (PRD group, 11 patients) or to receive PRD with PTX (10 mg/kg/day) (PTX group, 11 patients); the control group included children with normal bone marrow (10 patients). Bone marrow aspiration (BMA) was performed at diagnosis (day -7) in all groups, and at day 0 (end of PRD window) for patients with ALL (PRD and PTX groups). Apoptosis was evaluated by flow cytometry (FC) using Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) stains. Statistical analysis was performed using the Mann-Whitney U test. Apoptotic index at day -7 was similar in all groups. However, at day 0 post-treatment, apoptosis was significantly higher in the PTX group than in the PRD group (p < 0.001). There were no serious adverse effects associated with PTX. PTX potentiates blast apoptosis induced by PRD in children with ALL during steroid window phase.

Protection of Pentoxifylline against Testis Injury Induced by Intermittent Hypobaric Hypoxia

PubMed Central

Yao, Chen; Li, Gang; Qian, Yeyong; Cai, Ming; Yin, Hong; Xiao, Li; Tang, Wei; Guo, Fengjie

2016-01-01

To investigate the effect of pentoxifylline (PTX) on spermatogenesis dysfunction induced by intermittent hypobaric hypoxia (IHH) and unveil the underlying mechanism, experimental animals were assigned to Control, IHH+Vehicle, and IHH+PTX groups and exposed to 4 cycles of 96 h of hypobaric hypoxia followed by 96 h of normobaric normoxia for 32 days. PTX was administered for 32 days. Blood and tissue samples were collected 7 days thereafter. Serum malondialdehyde levels were used to assess lipid peroxidation; ferric-reducing antioxidant power (FRAP), superoxide dismutase, and catalase and glutathione peroxidase enzyme activities were assessed to determine antioxidant capacity in various samples. Testis histopathology was assessed after hematoxylin-eosin staining by Johnsen's testicular scoring system. Meanwhile, testosterone synthase and vimentin amounts were assessed by immunohistochemistry. Sperm count, motility, and density were assessed to determine epididymal sperm quality. IHH treatment induced significant pathological changes in testicular tissue and enhanced serum lipid peroxide levels, while reducing serum FRAP, antioxidant enzyme activities, and testosterone synthase expression. Moreover, IHH impaired epididymal sperm quality and vimentin structure in Sertoli cells. Oral administration of PTX improved the pathological changes in the testis. IHH may impair spermatogenesis function of testicular tissues by inducing oxidative stress, but this impairment could be attenuated by administration of PTX. PMID:27642493

[Platelet hyperreactivity and antiaggregatory properties of nootropic drugs under conditions of alloxan-induced diabetes in rats].

PubMed

Zhiliuk, V I; Levykh, A É; Mamchur, V I

2012-01-01

The effects of nootropic drugs (noopept, pentoxifylline, piracetam, pramiracetam, Ginkgo biloba extract, entrop, cerebrocurin and citicoline) on platelet aggregation in rats with experimental diabetes have been studied. It is established that all these drugs exhibit an inhibitory action of various degrees against platelet hyperreactivity under conditions of chronic hyperglycemia. The maximum universality of the antiaggregatory action is characteristic of pramiracetam, entrop and Ginkgo biloba extract.

Ex Vivo Host and Parasite Response to Antileishmanial Drugs and Immunomodulators

PubMed Central

McMahon-Pratt, Diane; Saravia, Nancy Gore

2015-01-01

Background Therapeutic response in infectious disease involves host as well as microbial determinants. Because the immune and inflammatory response to Leishmania (Viannia) species defines the outcome of infection and efficacy of treatment, immunomodulation is considered a promising therapeutic strategy. However, since Leishmania infection and antileishmanial drugs can themselves modulate drug transport, metabolism and/or immune responses, immunotherapeutic approaches require integrated assessment of host and parasite responses. Methodology To achieve an integrated assessment of current and innovative therapeutic strategies, we determined host and parasite responses to miltefosine and meglumine antimoniate alone and in combination with pentoxifylline or CpG 2006 in peripheral blood mononuclear cells (PBMCs) of cutaneous leishmaniasis patients. Parasite survival and secretion of TNF-α, IFN-γ, IL-10 and IL-13 were evaluated concomitantly in PBMCs infected with Luc-L. (V.) panamensis exposed to meglumine antimoniate (4, 8, 16, 32 and 64 μg SbV/mL) or miltefosine (2, 4, 8, 16 and 32 μM HePC). Concentrations of 4 μM of miltefosine and 8 μg SbV/mL were selected for evaluation in combination with immunomodulators based on the high but partial reduction of parasite burden by these antileishmanial concentrations without affecting cytokine secretion of infected PBMCs. Intracellular parasite survival was determined by luminometry and cytokine secretion measured by ELISA and multiplex assays. Principal Findings Anti- and pro-inflammatory cytokines characteristic of L. (V.) panamensis infection were evaluable concomitantly with viability of Leishmania within monocyte-derived macrophages present in PBMC cultures. Both antileishmanial drugs reduced the parasite load of macrophages; miltefosine also suppressed IL-10 and IL-13 secretion in a dose dependent manner. Pentoxifylline did not affect parasite survival or alter antileishmanial effects of miltefosine or meglumine antimoniate. However, pentoxifylline diminished secretion of TNF-α, IFN-γ and IL-13, cytokines associated with the outcome of infection by species of the Viannia subgenus. Exposure to CpG diminished the leishmanicidal effect of meglumine antimoniate, but not miltefosine, and significantly reduced secretion of IL -10, alone and in combination with either antileishmanial drug. IL-13 increased in response to CpG plus miltefosine. Conclusions and Significance Human PBMCs allow integrated ex vivo assessment of antileishmanial treatments, providing information on host and parasite determinants of therapeutic response that may be used to tailor therapeutic strategies to optimize clinical resolution. PMID:26024228

Recurrent cutaneous leishmaniasis*

PubMed Central

Gomes, Ciro Martins; Damasco, Fabiana dos Santos; de Morais, Orlando Oliveira; de Paula, Carmen Déa Ribeiro; Sampaio, Raimunda Nonata Ribeiro

2013-01-01

We present a case of an 18-year-old male patient who, after two years of inappropriate treatment for cutaneous leishmaniasis, began to show nodules arising at the edges of the former healing scar. He was immune competent and denied any trauma. The diagnosis of recurrent cutaneous leishmaniasis was made following positive culture of aspirate samples. The patient was treated with N-methylglucamine associated with pentoxifylline for 30 days. Similar cases require special attention mainly because of the challenges imposed by treatment. PMID:23793208

Dextran Sulfate Sodium-Induced Colonic Histopathology, but not Altered Epithelial Ion Transport, Is Reduced by Inhibition of Phosphodiesterase Activity

PubMed Central

Diaz-Granados, Natalia; Howe, Kathryn; Lu, Jun; McKay, Derek M.

2000-01-01

Inhibition of phosphodiesterase (PDE) activity is beneficial in models of arthritis and airway inflammation. Here we assessed the ability of PDE inhibitors to modulate colitis by exposing mice to 4% (w/v) dextran sulfate sodium (DSS) drinking water for 5 days with or without rolipram, an inhibitor of PDE type 4, or the nonselective PDE inhibitor, pentoxifylline (both at 5 mg/kg, i.p., twice daily). Controls received saline, vehicle, or drug only. Colonic histology, myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) levels, and epithelial ion transport (baseline and stimulated by electrical nerve stimulation, carbachol, and forskolin) were examined. DSS-treated mice displayed a variable diarrhea, significant histopathology in the mid-distal colon, elevated MPO activity, and reduced (>50%) responses to all three pro-secretory stimuli. Treatment with rolipram, and to a lesser extent pentoxifylline, significantly reduced the severity of the colonic histopathology and MPO levels. Neither PDE inhibitor had any affect on the diminished ion transport events caused by DSS-induced colitis. However, although stimulated ion transport events were still reduced 3 days after DSS treatment, colonic segments from DSS + rolipram-treated mice displayed enhanced recovery in their secretory responsiveness, particularly to carbachol. These findings indicate that specific PDE4 inhibition can significantly reduce the tissue damage that accompanies colitis and enhance recovery of normal colonic function. PMID:10854237

Multilayered Polysaccharide Nanofilms for Controlled Delivery of Pentoxifylline and Possible Treatment of Chronic Venous Ulceration.

PubMed

Stana, Jan; Stergar, Janja; Gradišnik, Lidija; Flis, Vojko; Kargl, Rupert; Fröhlich, Eleonore; Stana Kleinschek, Karin; Mohan, Tamilselvan; Maver, Uroš

2017-09-11

Local drug delivery systems made from nontoxic polysaccharide nanofilms have an enormous potential in wound care. A detailed understanding of the structural, surface, physicochemical, and cytotoxic properties of such systems is crucial to design clinically efficacious materials. Herein, we fabricated polysaccharide-based nanofilms onto either a 2D model (SiO 2 and Au sensors) or on nonwoven alginate 3D substrates using an alternating assembly of N,N,N-trimethylchitosan (TMC) and alginic acid (ALG) by a spin-assisted layer-by-layer (LbL) technique. These TMC/ALG multilayered nanofilms are used for a uniform encapsulation and controlled release of pentoxifylline (PTX), a potent anti-inflammatory drug for treatment of the chronic venous ulceration. We show a tailorable film growth and mass, morphology, as well as surface properties (charge, hydrophilicity, porosity) of the assembled nanofilms through control of the coating during the spin-assisted assembly. The uniform distribution of the encapsulated PTX in the TMC/ALG nanofilms is preserved even with when the amount of the incorporated PTX increases. The PTX release mechanism from the model and real systems is studied in detail and is very comparable for both systems. Finally, different cell-based assays illustrated the potential of the TMC/ALG multilayer system in wound care (e.g., treatment chronic venous ulceration) applications, including a decrease of TNF-α secretion, a common indicator of inflammation.

Design and evaluation of effervescent floating tablets based on hydroxyethyl cellulose and sodium alginate using pentoxifylline as a model drug

PubMed Central

Rahim, Safwan Abdel; Carter, Paul A; Elkordy, Amal Ali

2015-01-01

The aim of this work was to design and evaluate effervescent floating gastro-retentive drug delivery matrix tablets with sustained-release behavior using a binary mixture of hydroxyethyl cellulose and sodium alginate. Pentoxifylline was used as a highly water-soluble, short half-life model drug with a high density. The floating capacity, swelling, and drug release behaviors of drug-loaded matrix tablets were evaluated in 0.1 N HCl (pH 1.2) at 37°C±0.5°C. Release data were analyzed by fitting the power law model of Korsmeyer–Peppas. The effect of different formulation variables was investigated, such as wet granulation, sodium bicarbonate gas-forming agent level, and tablet hardness properties. Statistical analysis was applied by paired sample t-test and one-way analysis of variance depending on the type of data to determine significant effect of different parameters. All prepared tablets through wet granulation showed acceptable physicochemical properties and their drug release profiles followed non-Fickian diffusion. They could float on the surface of dissolution medium and sustain drug release over 24 hours. Tablets prepared with 20% w/w sodium bicarbonate at 50–54 N hardness were promising with respect to their floating lag time, floating duration, swelling ability, and sustained drug release profile. PMID:25848220

The Role and Regulation of TNF-Alpha in Normal Rat Mammary Gland During Development and in Breast Cancer.

DTIC Science & Technology

1996-07-01

autocrine synthesis of TNFcx by the MEC as well. Normally, there is strict control of the expression of this cytokine; however, it is possible that any...1,2-benz-anthracene (DMBA) (Sigma, St. Louis, MO) (in corn oil) p.o. using standard protocols (30) or via i.p. injection of 1-methyl-l- nitrosourea ...Beutler, B. Dexamethasone and pentoxifylline inhibit endotoxin- induced cachectin/tumor necrosis factor synthesis at separate points in the signalling

Noncompetitive blocking of human GLUT1 hexose transporter by methylxanthines reveals an exofacial regulatory binding site.

PubMed

Ojeda, Paola; Pérez, Alejandra; Ojeda, Lorena; Vargas-Uribe, Mauricio; Rivas, Coralia I; Salas, Monica; Vera, Juan Carlos; Reyes, Alejandro M

2012-09-01

Glucose transporter (GLUT)1 has become an attractive target to block glucose uptake in malignant cells since most cancer cells overexpress GLUT1 and are sensitive to glucose deprivation. Methylxanthines are natural compounds that inhibit glucose uptake; however, the mechanism of inhibition remains unknown. Here, we used a combination of binding and glucose transport kinetic assays to analyze in detail the effects of caffeine, pentoxifylline, and theophylline on hexose transport in human erythrocytes. The displacement of previously bound cytochalasin B revealed a direct interaction between the methylxanthines and GLUT1. Methylxanthines behave as noncompetitive blockers (inhibition constant values of 2-3 mM) in exchange and zero-trans efflux assays, whereas mixed inhibition with a notable uncompetitive component is observed in zero-trans influx assays (inhibition constant values of 5-12 mM). These results indicate that methylxanthines do not bind to either exofacial or endofacial d-glucose-binding sites but instead interact at a different site accessible by the external face of the transporter. Additionally, infinite-cis exit assays (Sen-Widdas assays) showed that only pentoxifylline disturbed d-glucose for binding to the exofacial substrate site. Interestingly, coinhibition assays showed that methylxanthines bind to a common site on the transporter. We concluded that there is a methylxanthine regulatory site on the external surface of the transporter, which is close but distinguishable from the d-glucose external site. Therefore, the methylxanthine moiety may become an attractive framework for the design of novel specific noncompetitive facilitative GLUT inhibitors.

Effects of late administration of pentoxifylline and tocotrienols in an image-guided rat model of localized heart irradiation.

PubMed

Sridharan, Vijayalakshmi; Tripathi, Preeti; Sharma, Sunil; Corry, Peter M; Moros, Eduardo G; Singh, Awantika; Compadre, Cesar M; Hauer-Jensen, Martin; Boerma, Marjan

2013-01-01

Radiation-induced heart disease (RIHD) is a long-term side effect of radiotherapy of intrathoracic, chest wall and breast tumors when radiation fields encompass all or part of the heart. Previous studies have shown that pentoxifylline (PTX) in combination with α-tocopherol reduced manifestations of RIHD in rat models of local heart irradiation. The relative contribution of PTX and α-tocopherol to these beneficial effects are not known. This study examined the effects of PTX alone or in combination with tocotrienols, forms of vitamin E with potential potent radiation mitigation properties. Rats received localized X-irradiation of the heart with an image-guided irradiation technique. At 3 months after irradiation rats received oral treatment with vehicle, PTX, or PTX in combination with a tocotrienol-enriched formulation. At 6 months after irradiation, PTX-treated rats showed arrhythmia in 5 out of 14 animals. PTX alone or in combination with tocotrienols did not alter cardiac radiation fibrosis, left ventricular protein expression of the endothelial markers von Willebrand factor and neuregulin-1, or phosphorylation of the signal mediators Akt, Erk1/2, or PKCα. On the other hand, tocotrienols reduced cardiac numbers of mast cells and macrophages, but enhanced the expression of tissue factor. While this new rat model of localized heart irradiation does not support the use of PTX alone, the effects of tocotrienols on chronic manifestations of RIHD deserve further investigation.

Effects of Late Administration of Pentoxifylline and Tocotrienols in an Image-Guided Rat Model of Localized Heart Irradiation

PubMed Central

Sridharan, Vijayalakshmi; Tripathi, Preeti; Sharma, Sunil; Corry, Peter M.; Moros, Eduardo G.; Singh, Awantika; Compadre, Cesar M.; Hauer-Jensen, Martin; Boerma, Marjan

2013-01-01

Radiation-induced heart disease (RIHD) is a long-term side effect of radiotherapy of intrathoracic, chest wall and breast tumors when radiation fields encompass all or part of the heart. Previous studies have shown that pentoxifylline (PTX) in combination with α-tocopherol reduced manifestations of RIHD in rat models of local heart irradiation. The relative contribution of PTX and α-tocopherol to these beneficial effects are not known. This study examined the effects of PTX alone or in combination with tocotrienols, forms of vitamin E with potential potent radiation mitigation properties. Rats received localized X-irradiation of the heart with an image-guided irradiation technique. At 3 months after irradiation rats received oral treatment with vehicle, PTX, or PTX in combination with a tocotrienol-enriched formulation. At 6 months after irradiation, PTX-treated rats showed arrhythmia in 5 out of 14 animals. PTX alone or in combination with tocotrienols did not alter cardiac radiation fibrosis, left ventricular protein expression of the endothelial markers von Willebrand factor and neuregulin-1, or phosphorylation of the signal mediators Akt, Erk1/2, or PKCα. On the other hand, tocotrienols reduced cardiac numbers of mast cells and macrophages, but enhanced the expression of tissue factor. While this new rat model of localized heart irradiation does not support the use of PTX alone, the effects of tocotrienols on chronic manifestations of RIHD deserve further investigation. PMID:23894340

Pentoxifylline prevents post-traumatic stress disorder induced memory impairment.

PubMed

Alzoubi, Karem H; Khabour, Omar F; Ahmed, Mohammed

2018-05-01

Posttraumatic stress disorder (PTSD) is a disabling prevalent and difficult-to-treat psychiatric disorder, which can develop after the exposure to severe traumatic events such as those occurring during wars and natural disasters. Pentoxifylline (PTX) is a potent antioxidant, which has an important role in prevention of cognitive dysfunctions. In the present study, the effect of PTX on memory impairment induced by PTSD was investigated using the rat animal model. PTSD-like behavior was induced in animals using a single-prolonged stress (SPS) rat model of PTSD (2 h restrain, 20 min forced swimming, 15 min rest, 1-2 min diethyl ether exposure). PTX was administered intraperitoneally at a dose of 100 mg/kg/day. Spatial learning and memory were assessed using the radial arm water maze (RAWM). Changes in oxidative stress biomarkers, brain derived neuroptrophic factor (BDNF), and epigenetics (histones) in the hippocampus following treatments were measured using enzymatic assays. The result revealed that SPS impaired both short- and long- term memory (P < 0.05). Use of PTX prevented memory impairment induced by SPS. Furthermore, PTX normalized SPS induced changes in the hippocampus GSH/GSSG ratio, activity of catalase, and glutathione peroxidase (GPx), BDNF, and certain histones levels. In conclusion, the SPS model of PTSD-like behavior induced memory impairment, whereas PTX prevented this impairment possibly through normalizing antioxidant mechanisms, BDNF and epigenetic changes in the hippocampus. Copyright © 2018 Elsevier Inc. All rights reserved.

Therapeutic effect of captopril, pentoxifylline, and cordyceps sinensis in pre-hepatic portal hypertensive rats.

PubMed

Ahmed, Ahmed F; El-Maraghy, Nabila N; Abdel Ghaney, Rasha H; Elshazly, Shimaa M

2012-01-01

Portal hypertension is an important and potentially fatal complication of liver disease whereby cellular and fibrotic alterations manifest to increase portal venous pressure. The aim of this study is to investigate the effect of captopril, pentoxifylline (PTX), and cordyceps sinensis in pre-hepatic portal hypertensive rats. Wistar male rats were divided at random into 3 main groups: the first group: control rats. The second group: sham-operated rats and the third group: prehepatic portal hypertensive rats (PHPHT) induced by regulated pre-hepatic portal vein ligation. After 14 days, Group 3 was subdivided into 5 subgroups. Subgroup (1): portal vein-ligated (PVL) was killed at once; Subgroup (2): received distilled water for 30 days (untreated PVL group); subgroups 3-5 were treated with captopril (60 mg/kg, orally); PTX (100 mg/kg, orally); and C. sinensis (200 mg/kg, orally), respectively, as a single daily dose for 30 days. Portal pressure, nitric oxide (NO), antioxidant enzymes, Liver enzymes, and creatinine levels were measured to evaluate the status of the liver state. Portal vein ligation produced significant increments in liver enzymes, NO, creatinine and portal pressure concomitant with significant decrements in glutathione content and superoxide dismutase activity. Treatment with captopril, PTX, and C. sinensis resulted in a significant reduction in liver enzymes, NO, creatinine and portal pressure and observable increase in antioxidant enzymes. captopril, PTX, and C. sinensis have promising effect in controlling PHPHT and reducing hyperdynamic circulatory state through reduction of portal pressure and NO level.

The effects of pentoxifylline adminstration on fracture healing in a postmenopausal osteoporotic rat model

PubMed Central

Vashghani Farahani, Mohammad Mahdi; Ahadi, Reza; Abdollahifar, Mohammadamin

2017-01-01

Previous studies report positive effects of pentoxifylline (PTX) alone or in combination with other drugs on some pathologic bone diseases as well as an ability to accelerate osteogensis and fracture healing in both animal models and human patients. The aim of this present study was to evaluate the effects of PTX administration on Hounsfield unit and bone strength at catabolic response (bone resorbing) of a fracture in an experimental rat model of ovariectomy induced osteoporosis (OVX-D). Thirty adult female rats were divided into groups as follows: 1 (OVX, control, no treatment); 2 (OVX, sham: daily distilled water); 3 (OVX, daily alendronate: 3 mg/kg); 4 (OVX, twice daily 100 mg/kg PTX) and 5 (OVX, PTX+alenderonate). OVX was induced by bilateral ovariectomy in all rats. A complete standardized osteotomy of the right femur was made after 3.5 months. PTX and alendronate treatments were performed for eight weeks. Then, rats were euthanized and had its right femur subjected to computerized tomography scanning for measuring Hounsfield unit; eventually, the samples were sent for a three point bending test for evaluation of the bone strength. Administration of PTX with 200 mg/kg and alendronate alone and in combination showed no significant alteration in Hounsfield unit and biomechanical properties of repairing callus of the complete osteotomy compared with the control group. Results showed increased bending stiffness and stress high load mean values of repairing complete osteotomy in PTX-treated rats compared to the control OVX-D. PMID:28400835

Pentoxifylline does not alter the response to inhaled grain dust.

PubMed

Jagielo, P J; Watt, J L; Quinn, T J; Knapp, H R; Schwartz, D A

1997-05-01

Pentoxifylline (PTX) has been shown to reduce sepsis-induced neutrophil sequestration in the lung and inhibit endotoxin-mediated release of tumor necrosis factor-alpha (TNF-alpha). Previously, we have shown that endotoxin appears to be the principal agent in grain dust causing airway inflammation and airflow obstruction following grain dust inhalation. To determine whether PTX affects the physiologic and inflammatory events following acute grain dust inhalation, 10 healthy, nonsmoking subjects with normal airway reactivity were treated with PTX or placebo (PL) followed by corn dust extract (CDE) inhalation (0.08 mL/kg), using a single-blinded, crossover design. Subjects received PTX (1,200 mg/d) or PL for 4 days prior to CDE inhalation and 400 mg PTX or PL on the exposure day. Both respiratory symptoms and declines in FEV1 and FVC occurred following CDE exposure in both groups, but there were no significant differences in the frequency of symptoms or percent declines from baseline in the FEV1 and FVC at any of the time points measured in the study. Elevations in peripheral blood leukocyte and neutrophil concentrations and BAL total cell, neutrophil, TNF-alpha, and interleukin-8 concentrations were measured 4 h following exposure to CDE in both the PTX- and PL-treated subjects, but no significant differences were found between treatment groups. These results suggest that pretreatment with PTX prior to inhalation of CDE, in the doses used in this study, does not alter the acute physiologic or inflammatory events following exposure to inhaled CDE.

Thyroxin Is Useful to Improve Sperm Motility

PubMed Central

Mendeluk, Gabriela Ruth; Rosales, Mónica

2016-01-01

Background The aim of this study was to evaluate the non-genomic action of thyroxin on sperm kinetic and its probable use to improve sperm recovery after applying an en- richment method like “swim-up” in comparison with the available one, pentoxifylline. Materials and Methods This is an experimental study. A total of 50 patients were re- cruited, followed by infertility consultation. Conventional sperm assays were performed according to World Health Organization criteria-2010 (WHO-2010). A Computer Aided Semen Analysis System was employed to assess kinetic parameters and concentrations. Number of the motile sperm recovered after preparation technique was calculated. Results Addition of T4 (0.002 µg/ml) to semen samples increased hypermotility at 20 minutes (control: 14.18 ± 5.1% vs. 17.66 ± 8.88%, P<0.03, data expressed as mean ± SD) and remained unchanged after 40 minutes. Significant differences were found in the motile sperm recovered after swim-up (control: 8.93×106 ± 9.52× 06vs. 17.20×106 ± 21.16×106, P<0.03), achieving all of the tested samples a desirable threshold value for artificial insemination outcome, while adding pentoxifylline increased the number of recovered sperm after swim-up in 60% of the studied cases. No synergism between two treatments could be determined. Conclusion We propose a new physiological tool to artificially improve insemination. The discussion opens windows to investigate unknown pathways involved in sperm ca- pacitation and gives innovative arguments to better understand infertility mechanisms. PMID:27441054

Novel methylxanthine derivative-mediated anti-inflammatory effects in inflammatory bowel disease

PubMed Central

Lee, In-Ah; Kamba, Alan; Low, Daren; Mizoguchi, Emiko

2014-01-01

Family 18 chitinases have a binding capacity with chitin, a polymer of N-acetylglucosamine. Recent studies strongly suggested that chitinase 3-like 1 (CHI3L1, also known as YKL-40) and acidic mammalian chitinase, the two major members of family 18 chitinases, play a pivotal role in the pathogenesis of inflammatory bowel disease (IBD), bronchial asthma and several other inflammatory disorders. Based on the data from high-throughput screening, it has been found that three methylxanthine derivatives, caffeine, theophylline, and pentoxifylline, have competitive inhibitory effects against a fungal family 18 chitinase by specifically interacting with conserved tryptophans in the active site of this protein. Methylxanthine derivatives are also known as adenosine receptor antagonists, phosphodiesterase inhibitors and histone deacetylase inducers. Anti-inflammatory effects of methylxanthine derivatives have been well-documented in the literature. For example, a beneficial link between coffee or caffeine consumption and type 2 diabetes as well as liver cirrhosis has been reported. Furthermore, theophylline has a long history of being used as a bronchodilator in asthma therapy, and pentoxifylline has an immuno-modulating effect for peripheral vascular disease. However, it is still largely unknown whether these methylxanthine derivative-mediated anti-inflammatory effects are associated with the inhibition of CHI3L1-induced cytoplasmic signaling cascades in epithelial cells. In this review article we will examine the above possibility and summarize the biological significance of methylxanthine derivatives in intestinal epithelial cells. We hope that this study will provide a rationale for the development of methylxanthine derivatives, in particular caffeine, -based anti-inflammatory therapeutics in the field of IBD and IBD-associated carcinogenesis. PMID:24574789

Novel methylxanthine derivative-mediated anti-inflammatory effects in inflammatory bowel disease.

PubMed

Lee, In-Ah; Kamba, Alan; Low, Daren; Mizoguchi, Emiko

2014-02-07

Family 18 chitinases have a binding capacity with chitin, a polymer of N-acetylglucosamine. Recent studies strongly suggested that chitinase 3-like 1 (CHI3L1, also known as YKL-40) and acidic mammalian chitinase, the two major members of family 18 chitinases, play a pivotal role in the pathogenesis of inflammatory bowel disease (IBD), bronchial asthma and several other inflammatory disorders. Based on the data from high-throughput screening, it has been found that three methylxanthine derivatives, caffeine, theophylline, and pentoxifylline, have competitive inhibitory effects against a fungal family 18 chitinase by specifically interacting with conserved tryptophans in the active site of this protein. Methylxanthine derivatives are also known as adenosine receptor antagonists, phosphodiesterase inhibitors and histone deacetylase inducers. Anti-inflammatory effects of methylxanthine derivatives have been well-documented in the literature. For example, a beneficial link between coffee or caffeine consumption and type 2 diabetes as well as liver cirrhosis has been reported. Furthermore, theophylline has a long history of being used as a bronchodilator in asthma therapy, and pentoxifylline has an immuno-modulating effect for peripheral vascular disease. However, it is still largely unknown whether these methylxanthine derivative-mediated anti-inflammatory effects are associated with the inhibition of CHI3L1-induced cytoplasmic signaling cascades in epithelial cells. In this review article we will examine the above possibility and summarize the biological significance of methylxanthine derivatives in intestinal epithelial cells. We hope that this study will provide a rationale for the development of methylxanthine derivatives, in particular caffeine, -based anti-inflammatory therapeutics in the field of IBD and IBD-associated carcinogenesis.

A Novel Compound Analgesic Cream (Ketamine, Pentoxifylline, Clonidine, DMSO) for Complex Regional Pain Syndrome Patients.

PubMed

Russo, Marc A; Santarelli, Danielle M

2016-01-01

Evidence suggests that complex regional pain syndrome (CRPS) is a manifestation of microvascular dysfunction. Topical combinations of α2-adrenergic receptor agonists or nitric oxide donors with phosphodiesterase or phosphatidic acid inhibitors formulated to treat microvascular dysfunction have been shown to reduce allodynia in a rat model of CRPS-I. Driven by these findings, we assessed the outcomes of CRPS patients treated with a compound analgesic cream (CAC) consisting of ketamine 10%, pentoxifylline 6%, clonidine 0.2%, and dimethyl sulfoxide 6% to 10%. An audit was conducted on 13 CRPS patients who trialed the CAC. A detailed report was compiled for each patient which comprised baseline characteristics, including CRPS description, previous treatments, and pain scores (numerical pain rating scale; 0 to 10). Recorded outcomes consisted of pain scores, descriptive outcomes, and concurrent medications/treatments, for which basic analysis was performed to determine the effectiveness of the CAC. Case reports are presented for 3 patients with varying outcomes. Nine patients (69%) reported pain/symptom reduction (4.4 ± 2.1 vs. 6.3 ± 1.9) with use of the CAC. Six patients reported sustained benefits after 2 months of CAC use, and 2 patients reported complete resolution of pain/symptoms: one had early CRPS-I and the other received a partial CRPS diagnosis. An otherwise medication refractory and intolerant patient found partial benefit with the CAC. These results demonstrate promise for this topical combination as a useful treatment in multimodal therapy for patients with CRPS, with the potential to resolve pain/symptoms in early CRPS patients. © 2015 World Institute of Pain.

Evaluation of the protective effect of pentoxifylline on carrageenan-induced chronic non-bacterial prostatitis in rats.

PubMed

Hajighorbani, Mahboobeh; Ahmadi-Hamedani, Mahmood; Shahab, Elaheh; Hayati, Farzad; Kafshdoozan, Khatereh; Keramati, Keivan; Amini, Amin Hossein

2017-06-01

Chronic non-bacterial prostatitis (CNP) is the most common type of prostatitis and oxidative stress (OS) was shown to be highly elevated in prostatitis patients. This study aimed to investigate the protective effect of pentoxifylline (PTX) on CNP induced by carrageenan in rats. Male adult Wistar rats (n = 30) were divided into control, CNP and three treatment groups (n = 6) including CNP + cernilton and CNP + PTX groups. CNP was induced by single intraprostatic injection of 1% carrageenan (100 µl). Rats in treatment groups received orally cernilton 100 mg/kg and PTX at 50 and 100 mg/kg 1 week after CNP induction for 21 days. Prostatic index (PI), prostatic specific antigen (PSA), tumor-necrosis factor alpha (TNF-α), serum lipid peroxidation (MDA), blood urea nitrogen, creatinine and histopathological changes were compared between groups. There were significant increase of PI, serum levels of PSA, TNF-α and MDA in CNP group at 29 day. In treatment groups, significant reduction in PI, serum levels of PSA, TNF-α, MDA and creatinine was observed especially in rats treated with dose of 50 mg/kg of PTX. In CNP group, histopathological changes of the prostate such as leucocyte infiltration, large involutions and projection into the lumen and reducing the volume of the lumen were observed as well. Whereas PTX, especially at dose of 50 mg/kg, could improve the above-mentioned changes remarkably in CNP treated rats. For the first time, our findings indicated that PTX improved CNP induced by carrageenan in rats.

The Effect of Pentoxifylline on bcl-2 Gene Expression Changes in Hippocampus after Ischemia-Reperfusion in Wistar Rats by a Quatitative RT-PCR Method

PubMed Central

Sari, Soyar; Hashemi, Mehrdad; Mahdian, Reza; Parivar, Kazem; Rezayat, Mehdi

2013-01-01

Ischemia-reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. Ischemia-reperfusion brain injury initiates an inflammatory response involving the expression of adhesion molecules and cytokines. Twenty–four male Wistar rats (250-300 g body wt) were used in this study. The animals were divided into four groups of 6 rats each: I: Control group that was subjected to ischemia-reperfusion, II: Ischemia-reperfusion group that was subjected to all surgical procedures, III: Drug group that received pentoxifylline (200, 400 and 600 mg/kg) 60 min before and after ischemia and IV: Vehicle group that received saline. Seventy two h after ischemia-reperfusion, the hippocampus was taken for studying the changes in bcl-2 gene expression. We used quantitative real-time PCR for the detection of bcl-2 gene expression in ischemia and drug groups and then compared them to normal samples. The results showed the gene dosage ratio of 0.66 and 1.5 for ischemia group and the drug groups, respectively. The results also showed the bcl-2 gene expression declined in ischemia group as compared to the drug group. Furthermore, we observed a significant difference in the bcl-2 gene expression between ischemia and drug groups. These findings are consistent with anti-apoptotic properties of bcl-2 gene. Furthermore this method provides a powerful tool for the investigators to study brain ischemia and respond to the treatment drugs with anti-apoptotic agents. PMID:24250655

Therapeutic Effect of Captopril, Pentoxifylline, and Cordyceps Sinensis in Pre-Hepatic Portal Hypertensive Rats

PubMed Central

Ahmed, Ahmed F.; El-Maraghy, Nabila N.; Ghaney, Rasha H. Abdel; Elshazly, Shimaa M.

2012-01-01

Background/Aim: Portal hypertension is an important and potentially fatal complication of liver disease whereby cellular and fibrotic alterations manifest to increase portal venous pressure. The aim of this study is to investigate the effect of captopril, pentoxifylline (PTX), and cordyceps sinensis in pre-hepatic portal hypertensive rats. Settings and Design: Wister male rats were divided at random into 3 main groups: the first group: control rats. The second group: sham-operated rats and the third group: prehepatic portal hypertensive rats (PHPHT) induced by regulated pre-hepatic portal vein ligation. After 14 days, Group 3 was subdivided into 5 subgroups. Subgroup (1): portal vein-ligated (PVL) was killed at once; Subgroup (2): received distilled water for 30 days (untreated PVL group); subgroups 3-5 were treated with captopril (60 mg/kg, orally); PTX (100 mg/kg, orally); and C. sinensis (200 mg/kg, orally), respectively, as a single daily dose for 30 days. Patients and Methods: Portal pressure, nitric oxide (NO), antioxidant enzymes, Liver enzymes, and creatinine levels were measured to evaluate the status of the liver state. Results: Portal vein ligation produced significant increments in liver enzymes, NO, creatinine and portal pressure concomitant with significant decrements in glutathione content and superoxide dismutase activity. Treatment with captopril, PTX, and C. sinensis resulted in a significant reduction in liver enzymes, NO, creatinine and portal pressure and observable increase in antioxidant enzymes. Conclusions: captopril, PTX, and C. sinensis have promising effect in controlling PHPHT and reducing hyperdynamic circulatory state through reduction of portal pressure and NO level. PMID:22626797

Horizon 2020 in Diabetic Kidney Disease: The Clinical Trial Pipeline for Add-On Therapies on Top of Renin Angiotensin System Blockade

PubMed Central

Perez-Gomez, Maria Vanessa; Sanchez-Niño, Maria Dolores; Sanz, Ana Belen; Martín-Cleary, Catalina; Ruiz-Ortega, Marta; Egido, Jesus; Navarro-González, Juan F.; Ortiz, Alberto; Fernandez-Fernandez, Beatriz

2015-01-01

Diabetic kidney disease is the most frequent cause of end-stage renal disease. This implies failure of current therapeutic approaches based on renin-angiotensin system (RAS) blockade. Recent phase 3 clinical trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced diabetic kidney disease failed to meet the primary endpoint or terminated on safety concerns, respectively. However, various novel strategies are undergoing phase 2 and 3 randomized controlled trials targeting inflammation, fibrosis and signaling pathways. Among agents currently undergoing trials that may modify the clinical practice on top of RAS blockade in a 5-year horizon, anti-inflammatory agents currently hold the most promise while anti-fibrotic agents have so far disappointed. Pentoxifylline, an anti-inflammatory agent already in clinical use, was recently reported to delay estimated glomerular filtration rate (eGFR) loss in chronic kidney disease (CKD) stage 3–4 diabetic kidney disease when associated with RAS blockade and promising phase 2 data are available for the pentoxifylline derivative CTP-499. Among agents targeting chemokines or chemokine receptors, the oral small molecule C-C chemokine receptor type 2 (CCR2) inhibitor CCX140 decreased albuminuria and eGFR loss in phase 2 trials. A dose-finding trial of the anti-IL-1β antibody gevokizumab in diabetic kidney disease will start in 2015. However, clinical development is most advanced for the endothelin receptor A blocker atrasentan, which is undergoing a phase 3 trial with a primary outcome of preserving eGFR. The potential for success of these approaches and other pipeline agents is discussed in detail. PMID:26239562

Edematogenic activity of a sulfated galactan from the red marine algae Gelidium crinale.

PubMed

Assreuy, Ana Maria Sampaio; Amorim, Renata Morais Ferreira; Brizeno, Luiz André Cavalcante; de Paulo Pereira, Lívia; de Sousa, Albertina Antonielly Sydney; Aragão, Gislei Frota; Pereira, Maria Gonçalves

2012-09-01

The red algae Gelidium crinale (Turner) Gaillon (Gelidiaceae), encountered along the Southeast and Northeast Brazilian sea coast, contains a sulfated galactan presenting a similar saccharide backbone compared to λ carrageenan. Inflammatory effects of other galactans were reported, but not for that obtained from G. crinale (SG-Gc). To investigate the in vivo edematogenic effect of SG-Gc in comparison to λ carrageenan. SG-Gc was isolated by ion exchange chromatography. Paw edema was induced by subcutaneous (s.c.) intraplantar injection of SG-Gc or λ carrageenan and evaluated by hydroplethysmometry. Data were expressed as the increase in paw volume subtracted from the basal volume or area under curve-AUC. To investigate the participation of early and late-phase inflammatory mediators, rats were treated with pyrilamine, compound 48/80, indomethacin, NG-nitro-L-arginine methyl ester (L-NAME), or pentoxifylline before SG-Gc. SG-Gc edematogenic effect was initiated at 0.5 h, peaked at 2 h (1.26 ± 0.05 mL) and lasted until 6 h (0.21 ± 0.03 mL), whereas the carrageenan-induced edema started at 1 h. The first phase (1-3 h) of SG-Gc-induced edema was 176 ± 15 (AUC) versus carrageenan (114.5 ± 14), whereas the second phase (3-5 h) was 95 ± 12 (AUC) versus carrageenan (117.5 ± 11). Treatment with compound 48/80, pyrilamine, indomethacin, L-NAME, and pentoxifylline inhibited the effect of SG-Gc by 32, 40, 69, 72, and 49%, respectively. SG-Gc and λ carrageenan induce different profile of inflammatory response in the paw edema model, that involves histamine, cytokines, prostaglandins, and nitric oxide (NO), but with different degree of participation.

The use of sulfasalazine and pentoxifylline (low-cost antitumour necrosis factor drugs) as adjuvant therapy for the treatment of pemphigus vulgaris: a comparative study.

PubMed

el-Darouti, M; Marzouk, S; Abdel Hay, R; el-Tawdy, A; Fawzy, M; Leheta, T; Gammaz, H; Al Gendy, N

2009-08-01

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)-alpha has been suggested to have a possible role in the mechanism underlying acantholysis. 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. 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-alpha 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. The serum level of TNF-alpha 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-alpha 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. 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-alpha, and this decrease was associated with rapid clinical improvement.

Combination Chemotherapy with Suboptimal Doses of Benznidazole and Pentoxifylline Sustains Partial Reversion of Experimental Chagas' Heart Disease

PubMed Central

Vilar-Pereira, Glaucia; Resende Pereira, Isabela; de Souza Ruivo, Leonardo Alexandre; Cruz Moreira, Otacilio; da Silva, Andrea Alice; Britto, Constança

2016-01-01

Chronic chagasic cardiomyopathy (CCC) progresses with parasite persistence, fibrosis, and electrical alterations associated with an unbalanced immune response such as high plasma levels of tumor necrosis factor (TNF) and nitric oxide (NO). Presently, the available treatments only mitigate the symptoms of CCC. To improve CCC prognosis, we interfered with the parasite load and unbalanced immune response using the trypanocidal drug benznidazole (Bz) and the immunoregulator pentoxifylline (PTX). C57BL/6 mice chronically infected with the Colombian strain of Trypanosoma cruzi and with signs of CCC were treated for 30 days with a suboptimal dose of Bz (25 mg/kg of body weight), PTX (20 mg/kg), or their combination (Bz plus PTX) and analyzed for electrocardiographic, histopathological, and immunological changes. Bz (76%) and Bz-plus-PTX (79%) therapies decreased parasite loads. Although the three therapies reduced myocarditis and fibrosis and ameliorated electrical alterations, only Bz plus PTX restored normal heart rate-corrected QT (QTc) intervals. Bz-plus-PTX-treated mice presented complementary effects of Bz and PTX, which reduced TNF expression (37%) in heart tissue and restored normal TNF receptor 1 expression on CD8+ T cells, respectively. Bz (85%) and PTX (70%) therapies reduced the expression of inducible nitric oxide synthase (iNOS/NOS2) in heart tissue, but only Bz (58%) reduced NO levels in serum. These effects were more pronounced after Bz-plus-PTX therapy. Moreover, 30 to 50 days after treatment cessation, reductions of the prolonged QTc and QRS intervals were sustained in Bz-plus-PTX-treated mice. Our findings support the importance of interfering with the etiological agent and immunological abnormalities to improve CCC prognosis, opening an opportunity for a better quality of life for Chagas' disease (CD) patients. PMID:27161638

The radiation-induced fibroatrophic process: therapeutic perspective via the antioxidant pathway.

PubMed

Delanian, Sylvie; Lefaix, Jean-Louis

2004-11-01

The radiation-induced fibroatrophic process (RIF) constitutes a late, local and unavoidable sequela to high-dose radiotherapy, traditionally considered irreversible. Today, this process is partly reversible, thanks to recent progress in understanding the physiopathology of the lesions it causes and the results of recent clinical trials using antioxidant therapy. This review includes a synthetic description of the static and dynamic features of the RIF process, as reflected by its clinical, instrumental and histopathological characteristics, and by its cellular and molecular regulation. Schematically, three successive clinical and histopathological phases can be distinguished: a pre-fibrotic aspecific inflammatory phase, a constitutive fibrotic cellular phase, and a matrix densification and remodelling phase, possibly ending in terminal tissular necrosis. The respective roles of the chief actors in the RIF process are defined, as well as their development with time. A fibroblastic stromal hypothesis is suggested revolving around a 'gravitational effect' exerted by the couple ROS (reactive oxygen species)--fibroblasts, and partly mediated by TGF-beta1. A variety of strategies have been tested for the management of RIF. In the light of the mechanisms described, a curative procedure has been proposed via the antioxidant pathway. In particular, it was showed that superoxide dismutase and combined pentoxifylline-tocopherol treatment enables the process of established radiation-induced fibroatrophy to be greatly reduced or even reversed, both in clinical practice and animal experiments. The efficacy of combined pentoxifylline-tocopherol treatment in superficial RIF was confirmed in a randomised clinical trial, and then in successful phase II trials especially in uterine fibroatrophy and osteoradionecrosis. It is of critical importance to evaluate these new management approaches in larger clinical trials and to improve the recording of results for better outcome analysis. Mechanistic studies are always necessary to improve understanding of the RIF process and the antifibrotic drug action.

Effects of topical combinations of clonidine and pentoxifylline on capsaicin-induced allodynia and postcapsaicin tourniquet-induced pain in healthy volunteers: a double-blind, randomized, controlled study.

PubMed

Ragavendran, J Vaigunda; Laferrière, André; Bennett, Gary J; Ware, Mark A; Gandhi, Wiebke; Bley, Keith; Schweinhardt, Petra; Coderre, Terence J

2016-10-01

This double-blind randomized controlled study was designed to evaluate the analgesic effects of topical treatments with clonidine (CLON) and pentoxifylline (PTX) tested alone or as low- and high-dose combinations in a human experimental model of pain. Of 69 healthy subjects aged 18 to 60 years, 23 each were randomly allocated to low-dose (0.04% + 2%) and high-dose (0.1% + 5%) CLON + PTX groups. Both of these groups also received their corresponding placebos in one of 2 treatment periods separated by at least 48 hours. Twenty-three additional subjects received either CLON (0.1%) or PTX (5%) as single drug treatments, in each of 2 treatment periods. Assessment of analgesic efficacy was based on allodynic effects of previous intraepidermal capsaicin injection, as well as postcapsaicin tourniquet-induced pain 50 minutes following capsaicin injection. Visual Analogue Scale (VAS) ratings of pain intensity and the area of dynamic mechanical allodynia were the primary outcome measures, whereas area of punctate mechanical allodynia (PMA) served as a secondary outcome measure. Topical treatments with high- or low-dose combinations significantly reduced VAS ratings compared with corresponding placebo treatments throughout the period of postcapsaicin tourniquet-induced pain. Importantly, the high-dose combination produced lower VAS ratings than CLON alone, which were lower than PTX alone. Results also revealed significant inhibition of postcapsaicin dynamic mechanical allodynia and PMA for the high-dose combination compared with placebo, and of PMA for CLON compared with the low-dose combination. Hence, the present data are supportive of further clinical investigation of the high-dose topical combination of CLON + PTX in complex regional pain syndrome and neuropathic pain patients, for which our preclinical data predict efficacy.

Sudden bilateral sensorineural hearing loss after intravenous cocaine injection: a case report and review of the literature.

PubMed

Stenner, Markus; Stürmer, Konrad; Beutner, Dirk; Klussmann, Jens Peter

2009-12-01

Little is known about the effects of intravenous abuse of cocaine, especially on the inner ear. We report on a 26-year-old man who presented to our outpatient department with a sudden severe hearing loss after intravenous injection of cocaine. The audiogram on admission showed symmetric air conduction levels up to 80 dB at 4 kHz. After treatment with intravenous sodium chloride, prednisolone, and pentoxifylline, the audiogram 2 days later showed a bilateral normacusis. A review of the literature on the topic is given and possible reasons for inner ear damages caused by cocaine are discussed.

Identification and preparation of sperm for ART.

PubMed

Mehta, Akanksha; Sigman, Mark

2014-02-01

State-of-the-art techniques attempt to select sperm with the best functional capacity to produce pregnancy and, subsequently, healthy offspring. A variety of approaches are now being evaluated. Future approaches may allow for selection of sperm based on sperm DNA integrity, degree of aneuploidy, or apoptosis. Other approaches involve attempting to improve the in vitro function of sperm with exposure to compounds such as pentoxifylline or platelet activating factor. In the future, we are likely to see significant improvements in the ability to select the best sperm for assisted-reproductive-technology procedures and the use of these procedures in routine clinical practice. Copyright © 2014 Elsevier Inc. All rights reserved.

Cardiovascular Drugs in Avian, Small Mammal, and Reptile Medicine.

PubMed

Fitzgerald, Brenna Colleen; Dias, Sara; Martorell, Jaume

2018-05-01

Cardiovascular disease, including congestive heart failure, pericardial disease, and atherosclerosis, is becoming increasingly better recognized in companion birds, small mammals, and reptiles. A wide range of medications is available to treat these conditions, including diuretics, vasodilators, positive and negative inotropes, antiarrhythmic agents, and pentoxifylline. This review systematically discusses each of these drug classes and their potential applications in exotic species. Although treatment approaches remain largely empirical and extrapolated from small animal and human medicine, the management strategies presented here have the potential to both maintain quality of life and extend survival time for the exotic cardiac patient. Copyright © 2018 Elsevier Inc. All rights reserved.

Effect of bucladesine, pentoxifylline, and H-89 as cyclic adenosine monophosphate analog, phosphodiesterase, and protein kinase A inhibitor on acute pain.

PubMed

Salehi, Forouz; Hosseini-Zare, Mahshid S; Aghajani, Haleh; Seyedi, Seyedeh Yalda; Hosseini-Zare, Maryam S; Sharifzadeh, Mohammad

2017-08-01

The aim of this study was to determine the effects of cyclic adenosine monophosphate (cAMP) and its dependent pathway on thermal nociception in a mouse model of acute pain. Here, we studied the effect of H-89 (protein kinase A inhibitor), bucladesine (Db-cAMP) (membrane-permeable analog of cAMP), and pentoxifylline (PTX; nonspecific phosphodiesterase (PDE) inhibitor) on pain sensation. Different doses of H-89 (0.05, 0.1, and 0.5 mg/100 g), PTX (5, 10, and 20 mg/100 g), and Db-cAMP (50, 100, and 300 nm/mouse) were administered intraperitoneally (I.p.) 15 min before a tail-flick test. In combination groups, we injected the first and the second compounds 30 and 15 min before the tail-flick test, respectively. I.p. administration of H-89 and PTX significantly decreased the thermal-induced pain sensation in their low applied doses. Db-cAMP, however, decreased the pain sensation in a dose-dependent manner. The highest applied dose of H-89 (0.5 mg/100 g) attenuated the antinociceptive effect of Db-cAMP in doses of 50 and 100 nm/mouse. Surprisingly, Db-cAMP decreased the antinociceptive effect of the lowest dose of H-89 (0.05 mg/100 g). All applied doses of PTX reduced the effect of 0.05 mg/100 g H-89 on pain sensation; however, the highest dose of H-89 compromised the antinociceptive effect of 20 mg/100 g dose of PTX. Co-administration of Db-cAMP and PTX increased the antinociceptive effect of each compound on thermal-induced pain. In conclusion, PTX, H-89, and Db-cAMP affect the thermal-induced pain by probably interacting with intracellular cAMP and cGMP signaling pathways and cyclic nucleotide-dependent protein kinases. © 2017 Société Française de Pharmacologie et de Thérapeutique.

Involvement of tumour necrosis factor-α in Clostridium perfringens β-toxin-induced plasma extravasation in mice

PubMed Central

Nagahama, M; Kihara, A; Kintoh, H; Oda, M; Sakurai, J

2008-01-01

Background and purpose: Clostridium perfringens beta-toxin, an important agent of necrotic enteritis, causes plasma extravasation due to the release of a tachykinin NK1 receptor agonist in mouse skin. In this study, we investigated the role of cytokines in beta-toxin-induced plasma extravasation. Experimental approach: Male Balb/c, C3H/HeN and C3H/HeJ mice were anaesthetized with pentobarbitone and beta-toxin was injected i.d. into shaved dorsal skin. SR140333, capsaicin, chlorpromazine and pentoxifylline were given as pretreatment when required before the injection of the toxin. Cytokines in the dorsal skin were measured by ELISA. Key results: Injection (i.d.) of beta-toxin induced a dose-dependent increase in dermal TNF-α and interleukin (IL)-1β levels with a concomitant increase in plasma extravasation, but not the release of IL-6. SR140333 and capsaicin significantly inhibited the toxin-induced release of TNF-α and IL-1β. The plasma extravasation and the release of TNF-α induced by beta-toxin were significantly inhibited by chlorpromazine and pentoxifylline which inhibit the release of TNF-α. The toxin-induced plasma extravasation in mouse skin was attenuated by pretreatment with a monoclonal antibody against TNF-α, but not anti-IL-1β. Furthermore, the toxin caused an increase in plasma extravasation in both C3H/HeN (TLR4-intact) and C3H/HeJ (TLR4-deficient) mice. In C3H/HeN mice, the toxin-induced leakage was not inhibited by pretreatment with anti-TLR4/MD-2 antibody. Conclusions and implications: These observations show that beta-toxin-induced plasma extravasation in mouse skin is related to the release of TNF-α via the mechanism involving tachykinin NK1 receptors, but not via TLR4. PMID:18264118

Efficacy and safety evaluation of pentoxifylline associated with other antioxidants in medical treatment of Peyronie’s disease: a case-control study

PubMed Central

Paulis, Gianni; Barletta, Davide; Turchi, Paolo; Vitarelli, Antonio; Dachille, Giuseppe; Fabiani, Andrea; Gennaro, Romano

2016-01-01

Peyronie’s disease (PD) is a chronic disorder involving the tunica albuginea surrounding the corpora cavernosa of the penis. A conservative treatment is indicated in the first stage of disease. The aim of this study was to assess the therapeutic impact and possible side effects of treatment with pentoxifylline (PTX) in combination with other antioxidants in 307 patients with early-stage PD. Patients were subdivided into three groups: A, B, and C. Both groups, A and B, comprising of 206 patients, underwent treatment, whereas Group C was the control group (n=101). Treatment lasted 6 months and included the following: Group A: PTX 400 mg twice a day + propolis 600 mg/d + blueberry 160 mg/d + vitamin E 600 mg/d + diclofenac 4% gel twice/a day + PTX 100 mg via perilesional penile injection/every other week (12 injections in all); Group B: the same treatment as Group A except for the penile PTX injections. After the 6-month treatment course, we obtained the following results: actual mean decrease in plaque volume −46.9% and −24.8% in Group A and B, respectively (P<0.0001); mean curvature reduction −10.1° and −4.8°, respectively (P,0.0001); resolution of pain in 67.6% and 67.2% of cases, respectively (P=0.961); recovery of normal penile rigidity in 56.09% and 23.5% of cases, respectively (P=0.005). After 6 months, progression of disease was observed in all patients belonging to Group C: plaque volume +123.3%; curvature +15.7°; no recovery of penile rigidity. The statistically significant results of our study show that multimodal treatment with PTX in association with other antioxidants and topical diclofenac is efficacious in treating early-stage PD. Furthermore, treatment proved to be more effective when PTX was administered both orally and by penile injection. No serious adverse effects occurred. PMID:26770906

Simultaneous determination of pentoxifylline, metabolites M1 (lisofylline), M4 and M5, and caffeine in plasma and dried blood spots for pharmacokinetic studies in preterm infants and neonates.

PubMed

Page-Sharp, Madhu; Strunk, Tobias; Salman, Sam; Hibbert, Julie; Patole, Sanjay K; Manning, Laurens; Batty, Kevin T

2017-11-30

Advances in bioanalytical methods are facilitating micro-volume and dried blood spot (DBS) analysis of drugs in biological matrices for pharmacokinetic studies in children and neonates. We sought to develop a UPLC-MS/MS assay for simultaneous measurement of caffeine, pentoxifylline (PTX) and three metabolites of PTX in both plasma and DBS. Caffeine, PTX, the metabolites M1 (lisofylline), M4 and M5, and the internal standards (caffeine-d 9 and PTX-d 6 ) were separated using a Waters Aquity T3 UPLC C 18 column and gradient mobile phase (water-methanol-formic acid). Retention times for caffeine, M5, M4, PTX and M1 were 1.6, 1.7, 1.9, 2.0 and 2.1min, respectively, with a run time of 5min. The precision (≤10%) and accuracy (≤15%) across the concentration range 0.1-50mg/L for caffeine, PTX and the three metabolites in plasma and DBS were within accepted limits, as were the limits of quantification (100μg/L for caffeine and 10μg/L for PTX, M1, M4 and M5). Caffeine, PTX and the metabolites were stable in DBS for >34days at room and refrigerated temperatures. Plasma and DBS samples were obtained from 24 preterm infants recruited into a clinical pharmacokinetic study of PTX. Paired analysis indicated that DBS concentrations were 9% lower than concurrent plasma concentrations for caffeine, 7% lower for PTX (consistent with the blood:plasma ratio) and 13% lower for M1 (lisofylline). The validated UPLC-MS/MS method is suitable for micro-volume plasma and DBS analysis of caffeine, PTX and its metabolites for pharmacokinetic studies in paediatric patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Role of cytokines (TNF-alpha, IL-1beta and KC) in the pathogenesis of CPT-11-induced intestinal mucositis in mice: effect of pentoxifylline and thalidomide.

PubMed

Melo, Maria Luisa P; Brito, Gerly A C; Soares, Rudy C; Carvalho, Sarah B L M; Silva, Johan V; Soares, Pedro M G; Vale, Mariana L; Souza, Marcellus H L P; Cunha, Fernando Q; Ribeiro, Ronaldo A

2008-04-01

Irinotecan (CPT-11) is an inhibitor of DNA topoisomerase I and is clinically effective against several cancers. A major toxic effect of CPT-11 is delayed diarrhea; however, the exact mechanism by which the drug induces diarrhea has not been established. Elucidate the mechanisms of induction of delayed diarrhea and determine the effects of the cytokine production inhibitor pentoxifylline (PTX) and thalidomide (TLD) in the experimental model of intestinal mucositis, induced by CPT-11. Intestinal mucositis was induced in male Swiss mice by intraperitoneal administration of CPT-11 (75 mg/kg) daily for 4 days. Animals received subcutaneous PTX (1.7, 5 and 15 mg/kg) or TLD (15, 30, 60 mg/kg) or 0.5 ml of saline daily for 5 and 7 days, starting 1 day before the first CPT-11 injection. The incidence of delayed diarrhea was monitored by scores and the animals were sacrificed on the 5th and 7th experimental day for histological analysis, immunohistochemistry for TNF-alpha and assay of myeloperoxidase (MPO) activity, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and KC ELISA. CPT-11 caused significant diarrhea, histopathological alterations (inflammatory cell infiltration, loss of crypt architecture and villus shortening) and increased intestinal tissue MPO activity, TNF-alpha, IL-1beta and KC level and TNF-alpha immuno-staining. PTX inhibited delayed diarrhea of mice submitted to intestinal mucositis and reduced histopathological damage, intestinal MPO activity, tissue level of TNF-alpha, IL-1beta and KC and TNF-alpha immuno-staining. TLD significantly reduced the lesions induced by CPT-11 in intestinal mucosa, decreased MPO activity, TNF-alpha tissue level and TNF-alpha immuno-staining, but did not reduce the severity of diarrhea. These results suggest an important role of TNF-alpha, IL-1beta and KC in the pathogenesis of intestinal mucositis induced by CPT-11.

Preventive Effect of Phosphodiesterase Inhibitor Pentoxifylline Against Medication-Related Osteonecrosis of the Jaw: An Animal Study.

PubMed

Yalcin-Ulker, Gül Merve; Cumbul, Alev; Duygu-Capar, Gonca; Uslu, Ünal; Sencift, Kemal

2017-11-01

The aim of this experimental study was to investigate the prophylactic effect of pentoxifylline (PTX) on medication-related osteonecrosis of the jaw (MRONJ). Female Sprague-Dawley rats (n = 33) received zoledronic acid (ZA) for 8 weeks to create an osteonecrosis model. The left mandibular second molars were extracted and the recovery period lasted 8 weeks before sacrifice. PTX was intraperitoneally administered to prevent MRONJ. The specimens were histopathologically and histomorphometrically evaluated. Histomorphometrically, between the control and ZA groups, there was no statistically significant difference in total bone volume (P = .999), but there was a statistically significant difference in bone ratio in the extraction sockets (P < .001). A comparison of the bone ratio of the ZA group with the ZA/PTX group (PTX administered after extraction) showed no statistically significant difference (P = .69), but there was a statistically significant difference with the ZA/PTX/PTX group (PTX administered before and after extraction; P = .008). Histopathologically, between the control and ZA groups, there were statistically significant differences for inflammation (P = .013), vascularization (P = .022), hemorrhage (P = .025), and regeneration (P = .008). Between the ZA and ZA/PTX groups, there were no statistically significant differences for inflammation (P = .536), vascularization (P = .642), hemorrhage (P = .765), and regeneration (P = .127). Between the ZA and ZA/PTX/PTX groups, there were statistically significant differences for inflammation (P = .017), vascularization (P = .04), hemorrhage (P = .044), and regeneration (P = .04). In this experimental model of MRONJ, it might be concluded that although PTX, given after tooth extraction, improves new bone formation that positively affects bone healing, it is not prophylactic. However, PTX given before tooth extraction is prophylactic. Therefore, PTX might affect healing in a positive way by optimizing the inflammatory response. Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Pentoxifylline effects on capacitation and fertility of stallion epididymal sperm.

PubMed

Guasti, P N; Monteiro, G A; Maziero, R R D; Carmo, M T; Dell'Aqua, J A; Crespilho, A M; Rifai, E A; Papa, F O

2017-04-01

The aims of this study were to determinate whether pentoxifylline (PTX) increases the motion parameters of fresh and frozen-thawed equine epididymal spermatozoa, to evaluate the tyrosine phosphorylation of frozen-thawed epididymal sperm in the presence of PTX and to determine whether the PTX-treatment of stallion epididymal sperm prior to freezing improves the fertility response of mares to a reduced number of spermatozoa per insemination dose. Fifty epididymis were flushed with a skim milk based extender with or without PTX. The pre-treatment with PTX enhanced the sperm motility after being harvested (P<0.05); however the freeze-thaw process did not alter the sperm kinematics between control and treated samples (P>0.05). Plasma membrane integrity did not differ between control and PTX group after recovery and after thawing (P>0.05), as observed in tyrosine phosphorylation, which the PTX treatment did not alter the percentage of tail-associated immunofluorescence of cryopreserved epididymal sperm (P>0.05). For the fertility trial, different insemination groups were tested: 800×10 6 epididymal sperm (C800); 100×10 6 epididymal sperm (C100); 100×10 6 epididymal sperm recovered in an extender containing PTX (PTX100). The conception rates for C800; C100 and PTX100 were 68.7% (11/16); 31.5% (5/16) and 50% (8/16), respectively. The conception rate did not differ among groups (P>0.05), however, a low number of animals was used in this study. A trend toward significance (P=0.07) was observed between C800 and C100 groups. In conclusion, PTX has no deleterious effect on sperm motility, viability and capacitation of cryopreserved stallion epididymal sperm. The conventional artificial insemination with 100×10 6 sperm recovered with PTX ensures acceptable conception rates and maximize the limited number of doses of cryopreserved stallion epididymal sperm. Copyright © 2017 Elsevier B.V. All rights reserved.

Pentoxifylline inhibits hypoxia-induced upregulation of tumor cell tissue factor and vascular endothelial growth factor.

PubMed

Amirkhosravi, A; Meyer, T; Warnes, G; Amaya, M; Malik, Z; Biggerstaff, J P; Siddiqui, F A; Sherman, P; Francis, J L

1998-10-01

Tissue factor (TF), the membrane glycoprotein that initiates blood coagulation, is constitutively expressed by many tumor cells and is implicated in peri-tumor fibrin deposition and hypercoagulability in cancer. Upregulation of tumor TF correlates with enhanced metastatic potential. Furthermore, TF has been colocalized with VEGF in breast cancer, specially at sites of early angiogenesis. There are no data on the effect of hypoxia on tumor cell TF expression. Since hypoxia is known to stimulate VEGF production, we studied whether this also induces tumor cell TF expression. Confluent monolayers of A375 melanoma, MCF-7 breast carcinoma and A549 lung carcinoma were cultured in either 95% air, 5% CO2 (normoxic) or 95% N2, 5% CO2 (hypoxic; 25-30 mmHg) for 24 h. Procoagulant activity (PCA) was measured by amidolytic and clotting assays, surface TF antigen by flow cytometry, early apoptosis by annexin V binding and VEGF levels in culture supernatants by ELISA. Hypoxia significantly increased tumor cell PCA in all three cell lines tested and TF antigen on A375 cells was increased four-fold (P <0.05). Pentoxifylline (PTX), a methylxanthine derivative, significantly inhibited the hypoxia-induced increase in PCA as well as VEGF release in all three cell lines tested. In A375 cells, PTX significantly inhibited TF antigen expression by both normoxic and hypoxic cells. Hypoxia induced a slight (5%) but not significant, increase in early apoptosis. Intravenous injection of hypoxic A375 cells into nude rats produced more pronounced thrombocytopenia (n = 5, P <0.01) and more lung metastases (n = 3, P <0.05) compared to normoxic cells. We conclude that hypoxia increases TF expression by malignant cells which enhances tumor cell-platelet binding and hematogenous metastasis. Hypoxia-induced upregulation of TF appears to parallel that of VEGF, although the mechanism remains unclear.

Studies on Pentoxifylline and Tocopherol Combination for Radiation-Induced Heart Disease in Rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu Hui; Department of Radiotherapy, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong; Xiong Mai

Purpose: To investigate whether the application of pentoxifylline (PTX) and tocopherol l (Vit. E) could modify the development of radiation-induced heart disease and downregulate the expression of transforming growth factor (TGF)-{beta}1mRNA in rats. Methods and Materials: A total of 120 Sprague-Dawley rats were separated into four groups: control group, irradiated group, experimental group 1, and experiment group 2. Supplementation was started 3 days before irradiation; in experimental group 1, injection of PTX (15 mg/kg/d) and Vit. E (5.5 mg/kg/d) continued till the 12th week postirradiation, whereas in experimental group 2 it was continued until the 24th week postirradiation. All ratsmore » were administrated a single dose of 20 Gy irradiation to the heart except the control group. Histopathologic evaluation was performed at various time points (Days 1, 2, 4, 8, and 12 and 24th week) up to 24 weeks after irradiation. Changes of levels of TGF-{beta}1 mRNA expression were also investigated at the same time points using competitive polymerase chain reaction. Results: Compared with the irradiated group, levels of TGF-{beta}1 mRNA of the rat hearts were relatively low in the two experimental groups on the 12th week postirradiation. In experimental group 1, there was a rebound expression of TGF-{beta}1 mRNA on the 24th week postirradiation, whereas that of the experimental group 2 remained low (p < 0.05). The proportions of collagen fibers of the two experimental groups were lower than that of irradiated group (p < 0.05). A rebound could be observed in the experimental group 1. Conclusion: PTX and Vit. E downregulated the expression of TGF-{beta}1 mRNA. The irradiated rat hearts showed a marked pathologic response to the drugs. The withdrawal of drugs in the 12th week postirradiation could cause rebound effects of the development of fibrosis.« less

Intralymphatic Histiocytosis: A Report of 2 Cases.

PubMed

Gómez-Sánchez, M E; Azaña-Defez, J M; Martínez-Martínez, M L; López-Villaescusa, M T

Intralymphatic histiocytosis is a benign condition characterized by poorly defined erythematous plaques (sometimes forming a reticular pattern) as well as the presence of nodules and vesicles. Its etiology and pathogenesis appear to be related to chronic inflammation in the affected area, prior surgery, or systemic disease, particularly rheumatoid arthritis. We report on 2 new cases, both associated with joint surgery in the affected area and osteoarticular disease (primary synovial osteochondromatosis and rheumatoid arthritis). This is a chronic disease and there is no specific treatment. Different treatment options were chosen in the 2 cases described. A spectacular response to treatment with oral pentoxifylline and topical tacrolimus was observed in 1 of the patients. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Present and Future in the Treatment of Diabetic Kidney Disease

PubMed Central

de Arriba, Gabriel

2015-01-01

Diabetic kidney disease is the leading cause of end-stage renal disease. Albuminuria is recognized as the most important prognostic factor for chronic kidney disease progression. For this reason, blockade of renin-angiotensin system remains the main recommended strategy, with either angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. However, other antiproteinuric treatments have begun to be studied, such as direct renin inhibitors or aldosterone blockers. Beyond antiproteinuric treatments, other drugs such as pentoxifylline or bardoxolone have yielded conflicting results. Finally, alternative pathogenic pathways are being explored, and emerging therapies including antifibrotic agents, endothelin receptor antagonists, or transcription factors show promising results. The aim of this review is to explain the advances in newer agents to treat diabetic kidney disease, along with the background of the renin-angiotensin system blockade. PMID:25945357

In Patients With Severe Alcoholic Hepatitis, Prednisolone Increases Susceptibility to Infection and Infection-Related Mortality, and Is Associated With High Circulating Levels of Bacterial DNA.

PubMed

Vergis, Nikhil; Atkinson, Stephen R; Knapp, Suzanne; Maurice, James; Allison, Michael; Austin, Andrew; Forrest, Ewan H; Masson, Steven; McCune, Anne; Patch, David; Richardson, Paul; Gleeson, Dermot; Ryder, Stephen D; Wright, Mark; Thursz, Mark R

2017-04-01

Infections are common in patients with severe alcoholic hepatitis (SAH), but little information is available on how to predict their development or their effects on patients. Prednisolone is advocated for treatment of SAH, but can increase susceptibility to infection. We compared the effects of infection on clinical outcomes of patients treated with and without prednisolone, and identified risk factors for development of infection in SAH. We analyzed data from 1092 patients enrolled in a double-blind placebo-controlled trial to evaluate the efficacy of treatment with prednisolone (40 mg daily) or pentoxifylline (400 mg 3 times each day) in patients with SAH. The 2 × 2 factorial design led to 547 patients receiving prednisolone; 546 were treated with pentoxifylline. The trial was conducted in the United Kingdom from January 2011 through February 2014. Data on development of infection were collected at evaluations performed at screening, baseline, weekly during admission, on discharge, and after 90 days. Patients were diagnosed with infection based on published clinical and microbiologic criteria. Risk factors for development of infection and effects on 90-day mortality were evaluated separately in patients treated with prednisolone (n = 547) and patients not treated with prednisolone (n = 545) using logistic regression. Pretreatment blood levels of bacterial DNA (bDNA) were measured in 731 patients. Of the 1092 patients in the study, 135 had an infection at baseline, 251 developed infections during treatment, and 89 patients developed an infection after treatment. There was no association between pentoxifylline therapy and the risk of serious infection (P = .084), infection during treatment (P = .20), or infection after treatment (P = .27). Infections classified as serious were more frequent in patients treated with prednisolone (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.27-2.92; P = .002). There was no association between prednisolone therapy and infection during treatment (OR, 1.04; 95% CI, 0.78-1.37; P = .80). However, a higher proportion (10%) of patients receiving prednisolone developed an infection after treatment than of patients not given prednisolone (6%) (OR, 1.70; 95% CI, 1.07-2.69; P = .024). Development of infection was associated with increased 90-day mortality in patients with SAH treated with prednisolone, independent of model for end-stage liver disease or Lille score (OR, 2.46; 95% CI, 1.41-4.30; P = .002). High circulating bDNA predicted infection that developed within 7 days of prednisolone therapy, independent of Model for End-Stage Liver Disease and white blood cell count (OR, 4.68; 95% CI, 1.80-12.17; P = .001). In patients who did not receive prednisolone, infection was not independently associated with 90-day mortality (OR, 0.94; 95% CI, 0.54-1.62; P = .82) or levels of bDNA (OR, 0.83; 95% CI, 0.39-1.75; P = .62). Patients with SAH given prednisolone are at greater risk for developing serious infections and infections after treatment than patients not given prednisolone, which may offset its therapeutic benefit. Level of circulating bDNA before treatment could identify patients at high risk of infection if given prednisolone; these data could be used to select therapies for patients with SAH. EudraCT no: 2009-013897-42; Current Controlled Trials no: ISRCTN88782125. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Sensitization of cervix cancer cells to Adriamycin by Pentoxifylline induces an increase in apoptosis and decrease senescence.

PubMed

Bravo-Cuellar, Alejandro; Ortiz-Lazareno, Pablo C; Lerma-Diaz, Jose M; Dominguez-Rodriguez, Jorge R; Jave-Suarez, Luis F; Aguilar-Lemarroy, Adriana; del Toro-Arreola, Susana; de Celis-Carrillo, Ruth; Sahagun-Flores, Jose E; de Alba-Garcia, Javier E Garcia; Hernandez-Flores, Georgina

2010-05-19

Chemotherapeutic drugs like Adriamycin (ADR) induces apoptosis or senescence in cancer cells but these cells often develop resistance and generate responses of short duration or complete failure. The methylxantine drug Pentoxifylline (PTX) used routinely in the clinics setting for circulatory diseases has been recently described to have antitumor properties. We evaluated whether pretreatment with PTX modifies apoptosis and senescence induced by ADR in cervix cancer cells. HeLa (HPV 18+), SiHa (HPV 16+) cervix cancer cells and non-tumorigenic immortalized HaCaT cells (control) were treated with PTX, ADR or PTX + ADR. The cellular toxicity of PTX and survival fraction were determinated by WST-1 and clonogenic assay respectively. Apoptosis, caspase activation and ADR efflux rate were measured by flow cytometry, senescence by microscopy. IkappaBalpha and DNA fragmentation were determinated by ELISA. Proapoptotic, antiapoptotic and senescence genes, as well as HPV-E6/E7 mRNA expression, were detected by time real RT-PCR. p53 protein levels were assayed by Western blot. PTX is toxic (WST-1), affects survival (clonogenic assay) and induces apoptosis in cervix cancer cells. Additionally, the combination of this drug with ADR diminished the survival fraction and significantly increased apoptosis of HeLa and SiHa cervix cancer cells. Treatments were less effective in HaCaT cells. We found caspase participation in the induction of apoptosis by PTX, ADR or its combination. Surprisingly, in spite of the antitumor activity displayed by PTX, our results indicate that methylxantine, per se does not induce senescence; however it inhibits senescence induced by ADR and at the same time increases apoptosis. PTX elevates IkappaBalpha levels. Such sensitization is achieved through the up-regulation of proapoptotic factors such as caspase and bcl family gene expression. PTX and PTX + ADR also decrease E6 and E7 expression in SiHa cells, but not in HeLa cells. p53 was detected only in SiHa cells treated with ADR. PTX is a good inducer of apoptosis but does not induce senescence. Furthermore, PTX reduced the ADR-induced senescence and increased apoptosis in cervix cancer cells.

Sensitization of cervix cancer cells to Adriamycin by Pentoxifylline induces an increase in apoptosis and decrease senescence

PubMed Central

2010-01-01

Background Chemotherapeutic drugs like Adriamycin (ADR) induces apoptosis or senescence in cancer cells but these cells often develop resistance and generate responses of short duration or complete failure. The methylxantine drug Pentoxifylline (PTX) used routinely in the clinics setting for circulatory diseases has been recently described to have antitumor properties. We evaluated whether pretreatment with PTX modifies apoptosis and senescence induced by ADR in cervix cancer cells. Methods HeLa (HPV 18+), SiHa (HPV 16+) cervix cancer cells and non-tumorigenic immortalized HaCaT cells (control) were treated with PTX, ADR or PTX + ADR. The cellular toxicity of PTX and survival fraction were determinated by WST-1 and clonogenic assay respectively. Apoptosis, caspase activation and ADR efflux rate were measured by flow cytometry, senescence by microscopy. IκBα and DNA fragmentation were determinated by ELISA. Proapoptotic, antiapoptotic and senescence genes, as well as HPV-E6/E7 mRNA expression, were detected by time real RT-PCR. p53 protein levels were assayed by Western blot. Results PTX is toxic (WST-1), affects survival (clonogenic assay) and induces apoptosis in cervix cancer cells. Additionally, the combination of this drug with ADR diminished the survival fraction and significantly increased apoptosis of HeLa and SiHa cervix cancer cells. Treatments were less effective in HaCaT cells. We found caspase participation in the induction of apoptosis by PTX, ADR or its combination. Surprisingly, in spite of the antitumor activity displayed by PTX, our results indicate that methylxantine, per se does not induce senescence; however it inhibits senescence induced by ADR and at the same time increases apoptosis. PTX elevates IκBα levels. Such sensitization is achieved through the up-regulation of proapoptotic factors such as caspase and bcl family gene expression. PTX and PTX + ADR also decrease E6 and E7 expression in SiHa cells, but not in HeLa cells. p53 was detected only in SiHa cells treated with ADR. Conclusion PTX is a good inducer of apoptosis but does not induce senescence. Furthermore, PTX reduced the ADR-induced senescence and increased apoptosis in cervix cancer cells. PMID:20482878

Prospective Randomized Trial of Enoxaparin, Pentoxifylline and Ursodeoxycholic Acid for Prevention of Radiation-Induced Liver Toxicity

PubMed Central

Seidensticker, Max; Seidensticker, Ricarda; Damm, Robert; Mohnike, Konrad; Pech, Maciej; Sangro, Bruno; Hass, Peter; Wust, Peter; Kropf, Siegfried; Gademann, Günther; Ricke, Jens

2014-01-01

Background/Aim Targeted radiotherapy of liver malignancies has found to be effective in selected patients. A key limiting factor of these therapies is the relatively low tolerance of the liver parenchyma to radiation. We sought to assess the preventive effects of a combined regimen of pentoxifylline (PTX), ursodeoxycholic acid (UDCA) and low-dose low molecular weight heparin (LMWH) on focal radiation-induced liver injury (fRILI). Methods and Materials Patients with liver metastases from colorectal carcinoma who were scheduled for local ablation by radiotherapy (image-guided high-dose-rate interstitial brachytherapy) were prospectively randomized to receive PTX, UDCA and LMWH for 8 weeks (treatment) or no medication (control). Focal RILI at follow-up was assessed using functional hepatobiliary magnetic resonance imaging (MRI). A minimal threshold dose, i.e. the dose to which the outer rim of the fRILI was formerly exposed to, was quantified by merging MRI and dosimetry data. Results Results from an intended interim-analysis made a premature termination necessary. Twenty-two patients were included in the per-protocol analysis. Minimal mean hepatic threshold dose 6 weeks after radiotherapy (primary endpoint) was significantly higher in the study treatment-group compared with the control (19.1 Gy versus 14.6 Gy, p = 0.011). Qualitative evidence of fRILI by MRI at 6 weeks was observed in 45.5% of patients in the treatment versus 90.9% of the control group. No significant differences between the groups were observed at the 12-week follow-up. Conclusions The post-therapeutic application of PTX, UDCA and low-dose LMWH significantly reduced the extent and incidence fRILI at 6 weeks after radiotherapy. The development of subsequent fRILI at 12 weeks (4 weeks after cessation of PTX, UDCA and LMWH during weeks 1–8) in the treatment group was comparable to the control group thus supporting the observation that the agents mitigated fRILI. Trial Registration EU clinical trials register 2008-002985-70 ClinicalTrials.gov NCT01149304 PMID:25393877

Immunotherapy in the management of sepsis.

PubMed

Sikora, Janusz Piotr

2002-01-01

This work presents the role of Gram-negative bacteria endotoxins, pro- and anti-inflammatory cytokines and reactive oxygen species (ROS) in the complex and not fully explained pathogenesis of sepsis. The so-called "respiratory burst" of neutrophils and the antioxidant mechanisms of the host are also discussed. The work focuses on possible approaches to the management of sepsis connected with immunotherapy. Neutralization of endotoxin lipopolysaccharide (LPS), anti-tumor necrosis factor alpha (TNF-alpha) therapy with monoclonal antibodies or pentoxifylline (PTXF), as well as soluble recombinant cytokine agonists and antagonists used in clinical trials are taken into consideration. In addition, cytokine manipulation therapy, anti-adhesion techniques, glucocorticoides and antioxidant barrier interference are also described. So far there has been no immunotherapy of sepsis in children of proven clinical efficacy, which prompts an aggressive examination of the immune system aimed at affecting its function.

[Use of pentoxifylline in pediatric patients with grade IV (OMS) lupus nephropathy who have received multiple treatments].

PubMed

Vázquez García, M J; Vargas Camaño, M E; Olalde Carmona, R

2000-01-01

Systemic Lupus Eritematosus is an autoimmune disease, the incidence in pediatric poblation in about 5%, and until 90% develop nephropathy. Included patients with lupic nephropathy grade IV (OMS) ages between 0 and 16 years old, multitreated, who administrated PTX. We take samples before treatment, during, and 4 month after, evaluating renal function and hepatic function. For female, tow male, promedium age 14.1 years old. Poteinuria get a significative p = 0.0012; hematuria was lowering its levels, While immune circulating complex, get too a significative p = 0.0050. In creatinine inverse showed an important modification of its pending. This results demonstrates, that PTX in nephritis lupic patients, helps to brake the habitual deterioration in renal function. Includes more patients for a long time of treatment, we'll get better results than this.

Novel treatment for radiation optic neuropathy with intravenous bevacizumab.

PubMed

Farooq, Osman; Lincoff, Norah S; Saikali, Nicolas; Prasad, Dheerendra; Miletich, Robert S; Mechtler, Laszlo L

2012-12-01

Radiation optic neuropathy is a devastating form of vision loss that can occur months to years after radiation therapy for tumors and other lesions located in close proximity to the visual pathways. We present the case of a 24-year-old woman who underwent external beam radiation for treatment of a tectal pilocytic astrocytoma, and 5 years later she developed bilateral radiation optic neuropathy and radiation necrosis of the right temporal lobe. We opted to treat her with intravenous bevacizumab with 3 doses every 3 weeks, as well as dexamethasone and pentoxifylline. After the first infusion of bevacizumab, the patient noted improvement in vision and color vision, and a follow-up magnetic resonance imaging study showed that the previous enhancement of the optic nerves and chiasm was diminishing. Her vision improved dramatically and has remained stable over a 3-year period.

Antioxidants for female subfertility.

PubMed

Showell, Marian G; Mackenzie-Proctor, Rebecca; Jordan, Vanessa; Hart, Roger J

2017-07-28

A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This may affect up to a quarter of all couples planning a child. It is estimated that for 40% to 50% of couples, subfertility may result from factors affecting women. Antioxidants are thought to reduce the oxidative stress brought on by these conditions. Currently, limited evidence suggests that antioxidants improve fertility, and trials have explored this area with varied results. This review assesses the evidence for the effectiveness of different antioxidants in female subfertility. To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women. We searched the following databases (from their inception to September 2016) with no language or date restriction: Cochrane Gynaecology and Fertility Group (CGFG) specialised register, the Cochrane Central Register of Studies (CENTRAL CRSO), MEDLINE, Embase, PsycINFO, CINAHL and AMED. We checked reference lists of appropriate studies and searched for ongoing trials in the clinical trials registers. We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment or treatment with another antioxidant, among women attending a reproductive clinic. We excluded trials comparing antioxidants with fertility drugs alone and trials that only included fertile women attending a fertility clinic because of male partner infertility. Two review authors independently selected eligible studies, extracted the data and assessed the risk of bias of the included studies. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates and adverse events. We pooled studies using a fixed-effect model, and calculated odds ratios (ORs) with 95% confidence intervals (CIs) for the dichotomous outcomes of live birth, clinical pregnancy and adverse events. We assessed the overall quality of the evidence by applying GRADE criteria. We included 50 trials involving 6510 women. Investigators compared oral antioxidants, including combinations of antioxidants, N-acetyl-cysteine, melatonin, L-arginine, myo-inositol, D-chiro-inositol, carnitine, selenium, vitamin E, vitamin B complex, vitamin C, vitamin D+calcium, CoQ10, pentoxifylline and omega-3-polyunsaturated fatty acids versus placebo, no treatment/standard treatment or another antioxidant.Very low-quality evidence suggests that antioxidants may be associated with an increased live birth rate compared with placebo or no treatment/standard treatment (OR 2.13, 95% CI 1.45 to 3.12, P > 0.001, 8 RCTs, 651 women, I 2 = 47%). This suggests that among subfertile women with an expected live birth rate of 20%, the rate among women using antioxidants would be between 26% and 43%.Very low-quality evidence suggests that antioxidants may be associated with an increased clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.52, 95% CI 1.31 to 1.76, P < 0.001, 26 RCTs, 4271 women, I 2 = 66%). This suggests that among subfertile women with an expected clinical pregnancy rate of 22%, the rate among women using antioxidants would be between 27% and 33%. Heterogeneity was moderately high.There was insufficient evidence to determine whether there was a difference between the groups in rates of miscarriage (OR 0.79, 95% CI 0.58 to 1.08, P = 0.14, 18 RCTs, 2834 women, I 2 = 23%, very low quality evidence). This suggests that, among subfertile women with an expected miscarriage rate of 7%, use of antioxidants would be expected to result in a miscarriage rate of between 4% and 7%. There was also insufficient evidence to determine whether there was a difference between the groups in rates of multiple pregnancy (OR 1.00, 95% CI 0.73 to 1.38, P = 0.98, 8 RCTs, 2163 women, I 2 = 4%, very low quality evidence). This suggests that among subfertile women with an expected multiple pregnancy rate of 8%, use of antioxidants would be expected to result in a multiple pregnancy rate between 6% and 11%. Likewise, there was insufficient evidence to determine whether there was a difference between the groups in rates of gastrointestinal disturbances (OR 1.55, 95% CI 0.47 to 5.10, P = 0.47, 3 RCTs, 343 women, I 2 = 0%, very low quality evidence). This suggests that among subfertile women with an expected gastrointestinal disturbance rate of 2%, use of antioxidants would be expected to result in a rate between 1% and 11%. Overall adverse events were reported by 35 trials in the meta-analysis, but there was insufficient evidence to draw any conclusions.Only one trial reported on live birth, clinical pregnancy or adverse effects in the antioxidant versus antioxidant comparison, and no conclusions could be drawn.Very low-quality evidence suggests that pentoxifylline may be associated with an increased clinical pregnancy rate compared with placebo or no treatment (OR 2.07, 95% CI 1.20 to 3.56, P = 0.009, 3 RCTs, 276 women, I 2 = 0%). This suggests that among subfertile women with an expected clinical pregnancy rate of 25%, the rate among women using pentoxifylline would be between 28% and 53%.There was insufficient evidence to determine whether there was a difference between the groups in rates of miscarriage (OR 1.34, 95% CI 0.46 to 3.90, P = 0.58, 3 RCTs, 276 women, I 2 = 0%) or multiple pregnancy (OR 0.78, 95% CI 0.20 to 3.09, one RCT, 112 women, very low quality evidence). This suggests that among subfertile women with an expected miscarriage rate of 4%, the rate among women using pentoxifylline would be between 2% and 15%. For multiple pregnancy, the data suggest that among subfertile women with an expected multiple pregnancy rate of 9%, the rate among women using pentoxifylline would be between 2% and 23%.The overall quality of evidence was limited by serious risk of bias associated with poor reporting of methods, imprecision and inconsistency. In this review, there was very low-quality evidence to show that taking an antioxidant may provide benefit for subfertile women, but insufficient evidence to draw any conclusions about adverse events. At this time, there is limited evidence in support of supplemental oral antioxidants for subfertile women.

Pentoxifylline, dexamethasone and azithromycin demonstrate distinct age-dependent and synergistic inhibition of TLR- and inflammasome-mediated cytokine production in human newborn and adult blood in vitro

PubMed Central

Dowling, David J.; Xu, Jianjin; Ozog, Lukasz S.; Mathew, Jaime A.; Chander, Avinash; Yin, Donglei; Levy, Ofer

2018-01-01

Introduction Neonatal inflammation, mediated in part through Toll-like receptor (TLR) and inflammasome signaling, contributes to adverse outcomes including organ injury. Pentoxifylline (PTX), a phosphodiesterase inhibitor which potently suppresses cytokine production in newborn cord blood, is a candidate neonatal anti-inflammatory agent. We hypothesized that combinations of PTX with other anti-inflammatory agents, the steroid dexamethasone (DEX) or the macrolide azithromycin (AZI), may exert broader, more profound and/or synergistic anti-inflammatory activity towards neonatal TLR- and inflammasome-mediated cytokine production. Methods Whole newborn and adult blood was treated with PTX (50–200 μM), DEX (10−10–10−7 M), or AZI (2.5–20 μM), alone or combined, and cultured with lipopolysaccharide (LPS) (TLR4 agonist), R848 (TLR7/8 agonist) or LPS/adenosine triphosphate (ATP) (inflammasome induction). Supernatant and intracellular cytokines, signaling molecules and mRNA were measured by multiplex assay, flow cytometry and real-time PCR. Drug interactions were assessed based on Loewe's additivity. Results PTX, DEX and AZI inhibited TLR- and/or inflammasome-mediated cytokine production in newborn and adult blood, whether added before, simultaneously or after TLR stimulation. PTX preferentially inhibited pro-inflammatory cytokines especially TNF. DEX inhibited IL-10 in newborn, and TNF, IL-1β, IL-6 and interferon-α in newborn and adult blood. AZI inhibited R848-induced TNF, IL-1β, IL-6 and IL-10, and LPS-induced IL-1β and IL-10. (PTX+DEX) synergistically decreased LPS- and LPS/ATP-induced TNF, IL-1β, and IL-6, and R848-induced IL-1β and interferon-α, while (PTX+AZI) synergistically decreased induction of TNF, IL-1β, and IL-6. Synergistic inhibition of TNF production by (PTX+DEX) was especially pronounced in newborn vs. adult blood and was accompanied by reduction of TNF mRNA and enhancement of IL10 mRNA. Conclusions Age, agent, and specific drug-drug combinations exert distinct anti-inflammatory effects towards TLR- and/or inflammasome-mediated cytokine production in human newborn blood in vitro. Synergistic combinations of PTX, DEX and AZI may offer benefit for prevention and/or treatment of neonatal inflammatory conditions while potentially limiting drug exposure and toxicity. PMID:29715306

Inhibition of TNF-α in hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by inhibiting neurohormonal excitation in spontaneously hypertensive rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Song, Xin-Ai; Jia, Lin-Lin; Cui, Wei

We hypothesized that chronic inhibition of tumor necrosis factor-alpha (TNF-α) in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), decreasing nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase activities, as well as restoring the neurotransmitters balance in the PVN of spontaneously hypertensive rats (SHR). Adult normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusion of a TNF-α blocker (pentoxifylline or etanercept) or vehicle for 4 weeks. SHR rats showed higher mean arterial pressure and cardiac hypertrophy compared with WKY rats, as indicated by increased whole heartmore » weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC) mRNA expressions. Compared with WKY rats, SHR rats had higher PVN levels of tyrosine hydroxylase, PICs, the chemokine monocyte chemoattractant protein-1 (MCP-1), NF-κB p65 activity, mRNA expressions of NOX-2 and NOX-4, and lower PVN levels of IL-10 and 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma norepinephrine. PVN infusion of pentoxifylline or etanercept attenuated all these changes in SHR rats. These findings suggest that SHR rats have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between pro- and anti-inflammatory cytokines in the PVN; and chronic inhibition of TNF-α in the PVN delays the progression of hypertension by restoring the balances of neurotransmitters and cytokines in the PVN, and attenuating PVN NF-κB p65 activity and oxidative stress, thereby attenuating hypertension-induced sympathetic hyperactivity and cardiac hypertrophy. - Highlights: • Spontaneously hypertensive rats exhibit neurohormonal excitation in the PVN. • PVN inhibition of TNF-α attenuates hypertension-induced cardiac hypertrophy. • PVN inhibition of TNF-α attenuates hypertension-induced neurohormonal excitation. • PVN inhibition of TNF-α attenuates hypertension-induced imbalance of cytokines. • PVN inhibition of TNF-α attenuates PVN NF-κB p65 activity and oxidative stress.« less

Selective isolation of gonyautoxins 1,4 from the dinoflagellate Alexandrium minutum based on molecularly imprinted solid-phase extraction.

PubMed

Lian, Ziru; Wang, Jiangtao

2017-09-15

Gonyautoxins 1,4 (GTX1,4) from Alexandrium minutum samples were isolated selectively and recognized specifically by an innovative and effective extraction procedure based on molecular imprinting technology. Novel molecularly imprinted polymer microspheres (MIPMs) were prepared by double-templated imprinting strategy using caffeine and pentoxifylline as dummy templates. The synthesized polymers displayed good affinity to GTX1,4 and were applied as sorbents. Further, an off-line molecularly imprinted solid-phase extraction (MISPE) protocol was optimized and an effective approach based on the MISPE coupled with HPLC-FLD was developed for selective isolation of GTX1,4 from the cultured A. minutum samples. The separation method showed good extraction efficiency (73.2-81.5%) for GTX1,4 and efficient removal of interferences matrices was also achieved after the MISPE process for the microalgal samples. The outcome demonstrated the superiority and great potential of the MISPE procedure for direct separation of GTX1,4 from marine microalgal extracts. Copyright © 2017. Published by Elsevier Ltd.

Simultaneous estimation of lisofylline and pentoxifylline in rat plasma by high performance liquid chromatography-photodiode array detector and its application to pharmacokinetics in rat.

PubMed

Italiya, Kishan S; Sharma, Saurabh; Kothari, Ishit; Chitkara, Deepak; Mittal, Anupama

2017-09-01

Lisofylline (LSF) is an anti-inflammatory and immunomodulatory agent with proven activity in serious infections associated with cancer chemotherapy, hyperoxia-induced acute lung injury, autoimmune disorders including type-1 diabetes (T1DM) and islet rejection after islet transplantation. It is also an active metabolite of another anti-inflammatory agent, Pentoxifylline (PTX). LSF bears immense therapeutic potential in multiple pharmacological activities and hence appropriate and accurate quantification of LSF is very important. Although a number of analytical methods for quantification of LSF and PTX have been reported for pharmacokinetics and metabolic studies, each of these have certain limitations in terms of large sample volume required, complex extraction procedure and/or use of highly sophisticated instruments like LC-MS/MS. The aim of current study is to develop a simple reversed-phase HPLC method in rat plasma for simultaneous determination of LSF and PTX with the major objective of ensuring minimum sample volume, ease of extraction, economy of analysis, selectivity and avoiding use of instruments like LC-MS/MS to ensure a widespread application of the method. A simple liquid-liquid extraction method using methylene chloride as extracting solvent was used for extracting LSF and PTX from rat plasma (200μL). Samples were then evaporated, reconstituted with mobile phase and injected into HPLC coupled with photo-diode detector (PDA). LSF, PTX and 3-isobutyl 1-methyl xanthine (IBMX, internal standard) were separated on Inertsil® ODS (C18) column (250×4.6mm, 5μm) with mobile phase consisting of A-methanol B-water (50:50v/v) run in isocratic mode at flow rate of 1mL/min for 15min and detection at 273nm. The method showed linearity in the concentration range of 50-5000ng/mL with LOD of 10ng/mL and LLOQ of 50ng/mL for both LSF and PTX. Weighted linear regression analysis was also performed on the calibration data. The mean absolute recoveries were found to be 80.47±3.44 and 80.89±3.73% for LSF and PTX respectively. The method was successfully applied for studying the pharmacokinetics of LSF and PTX after IV bolus administration at dose of 25mg/kg in Wistar rat. In conclusion, a simple, sensitive, accurate and precise reversed-phase HPLC-UV method was established for simultaneous determination of LSF and PTX in rat plasma. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of acetylic salicylic acid and pentoxifylline on the efficacy of intravesical BCG therapy in orthotopic murine bladder cancer (MB49).

PubMed

Günther, J H; Frambach, M; Deinert, I; Brandau, S; Jocham, D; Böhle, A

1999-05-01

Intravesical immunotherapy with bacillus Calmette-Guerin (BCG), which has become the gold standard in the adjuvant treatment of superficial bladder cancer, is hampered by local side effects. Anti-inflammatory drugs may be helpful, but as an undesired side effect, therapeutic efficacy of BCG might be impaired. Therefore, we investigated the effects of anti-inflammatory drugs on the efficacy of intravesical BCG in an animal model. Syngenic tumor cells were implanted into the bladders of 75 mice according to our modification of the method. Mice were randomized to 5 groups with 15 animals each and treated with phosphate buffered saline (PBS), group 1; BCG, group 2; BCG + acetylic salicylic acid (ASA), group 3; BCG + pentoxifylline (POF), group 4; autoclaved BCG (aBCG), group 5. Intravesical instillation of 1.35 mg. BCG was initiated one day after tumor inoculation and repeated in weekly intervals for 4 instillations altogether. ASA and POF in doses of 200 mg./kg. and 150 mg./kg., respectively, were given continuously with the drinking water starting at the first instillation. Autoclaved BCG served as control for the importance of viability and was given at the same dose as viable BCG. Mice were monitored for survival, gross hematuria and body weight and after 28 days evaluated for bladder weight and tumor occurrence. Autoclaved BCG and PBS had no effect on tumor growth, whereas animals treated with viable BCG alone and in combination with POF and ASA, respectively, showed a significant reduction in bladder weight: PBS, 248 mg.; BCG, 140 mg. (p = 0.0009); BCG + ASA, 123 mg. (p = 0.0001); BCG + POF, 145 mg. (p = 0.0004); autoclaved BCG, 283 mg. (p = 0.21). Mice treated with BCG, BCG + ASA and BCG + POF showed a significantly higher proportion of survival until day 28 as compared to PBS alone. Autoclaved BCG had no therapeutic efficacy (Kaplan-Meier method/log rank test: BCG, p = 0.0053; BCG + ASA, p = 0.0044; BCG + POF, p = 0.0027; aBCG, p = 0.33). No significant differences among the 3 groups treated with viable BCG, with or without anti-inflammatory drugs, regarding bladder weight and survival were detectable. The efficacy of BCG therapy in murine orthotopic bladder cancer is dependent on BCG viability and is not compromised by ASA or POF. Clinical trials to evaluate the efficacy of routine ASA or POF to reduce BCG side effects in patients, using self-assessment criteria, should be initiated.

Effect of pentoxifylline on preventing acute kidney injury after cardiac surgery by measuring urinary neutrophil gelatinase - associated lipocalin.

PubMed

Barkhordari, Khosro; Karimi, Abbasali; Shafiee, Akbar; Soltaninia, Hasan; Khatami, Mohammad Reza; Abbasi, Kiomars; Yousefshahi, Fardin; Haghighat, Babak; Brown, Virginia

2011-01-19

Based on Acute Kidney Injury Network (AKIN) criteria, we considered acute kidney injury (AKI) as an absolute increase in the serum creatinine (sCr) level of more than or equal to 0.3 mg/dl or 50%. The introduction of Urinary neutrophil gelatinase-associated lipocalin (UNGAL) has conferred earlier diagnosis of AKI. Pentoxifylline (PTX), a non-specific phosphodiesterase inhibitor, can suppress the production of some factors of inflammatory response and presumably prevent AKI. We examined the PTX on the development of AKI in cardiac surgery patients by measuring the levels of UNGAL. We performed a double blind randomized clinical trial, enrolling 28 consecutive patients undergoing elective coronary artery bypass graft (CABG) surgery. Patients were divided into two groups, one to receive PTX 5 mg/kg intravenous bolus injection, followed by 1.5 mg/kg/h continuous intravenous infusion until 3 hours after cessation of CPB and the other group received placebo. UNGAL was measured before, 3 and 24 hours after surgery. In addition serum creatinine was measured before and 24, 48, 72 and 96 hours after surgery and C-reactive protein (CRP) only 24 hours postoperatively. Both groups did not differ in demographic and baseline characteristics. 12 patients developed AKI 48 hours after surgery; 5 of them were in the intervention group and 7 in the control group (p= 0.445). There was an increase of UNGAL in both groups postoperatively, although not significant. Mean sCr was significantly increased in the control group at 24 and 48 hours after surgery (24-h mean: 0.79 ± 0.18 mg/dl vs. 1.03 ± 0.43 mg/dl, P value = 0.02; 48-h mean: 1.17 ± 0.24 mg/dl vs. 0.98 ± 0.20 mg/dl, P value = 0.03, respectively). PTX had a positive effect in preventing AKI reflecting in changes in sCr, and the increase of UNGAL was consistent with the emergence of AKI (Pearson's correlation = 0.30). Our study demonstrates a weak correlation between UNGAL and sCr after cardiac surgery. The rise of UNGAL in these patients may be reduced by administration of PTX although we did not show significance. PTX could reduce the occurrence of AKI as determined by attenuation of sCr rise without causing hemodynamic instability or increased bleeding. Overall, we suggest future studies with larger sample sizes to elucidate this effect and determine the different aspects of administrating PTX. ISRCTN: IRCT138807302622N1.

Preparation of silica nanoparticles loaded with nootropics and their in vivo permeation through blood-brain barrier.

PubMed

Jampilek, Josef; Zaruba, Kamil; Oravec, Michal; Kunes, Martin; Babula, Petr; Ulbrich, Pavel; Brezaniova, Ingrid; Opatrilova, Radka; Triska, Jan; Suchy, Pavel

2015-01-01

The blood-brain barrier prevents the passage of many drugs that target the central nervous system. This paper presents the preparation and characterization of silica-based nanocarriers loaded with piracetam, pentoxifylline, and pyridoxine (drugs from the class of nootropics), which are designed to enhance the permeation of the drugs from the circulatory system through the blood-brain barrier. Their permeation was compared with non-nanoparticle drug substances (bulk materials) by means of an in vivo model of rat brain perfusion. The size and morphology of the nanoparticles were characterized by transmission electron microscopy. The content of the drug substances in silica-based nanocarriers was analysed by elemental analysis and UV spectrometry. Microscopic analysis of visualized silica nanocarriers in the perfused brain tissue was performed. The concentration of the drug substances in the tissue was determined by means of UHPLC-DAD/HRMS LTQ Orbitrap XL. It was found that the drug substances in silica-based nanocarriers permeated through the blood brain barrier to the brain tissue, whereas bulk materials were not detected in the brain.

Preparation of Silica Nanoparticles Loaded with Nootropics and Their In Vivo Permeation through Blood-Brain Barrier

PubMed Central

Zaruba, Kamil; Kunes, Martin; Ulbrich, Pavel; Brezaniova, Ingrid; Triska, Jan; Suchy, Pavel

2015-01-01

The blood-brain barrier prevents the passage of many drugs that target the central nervous system. This paper presents the preparation and characterization of silica-based nanocarriers loaded with piracetam, pentoxifylline, and pyridoxine (drugs from the class of nootropics), which are designed to enhance the permeation of the drugs from the circulatory system through the blood-brain barrier. Their permeation was compared with non-nanoparticle drug substances (bulk materials) by means of an in vivo model of rat brain perfusion. The size and morphology of the nanoparticles were characterized by transmission electron microscopy. The content of the drug substances in silica-based nanocarriers was analysed by elemental analysis and UV spectrometry. Microscopic analysis of visualized silica nanocarriers in the perfused brain tissue was performed. The concentration of the drug substances in the tissue was determined by means of UHPLC-DAD/HRMS LTQ Orbitrap XL. It was found that the drug substances in silica-based nanocarriers permeated through the blood brain barrier to the brain tissue, whereas bulk materials were not detected in the brain. PMID:26075264

Mustard vesicant-induced lung injury: Advances in therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weinberger, Barry, E-mail: bweinberger@northwell.e

Most mortality and morbidity following exposure to vesicants such as sulfur mustard is due to pulmonary toxicity. Acute injury is characterized by epithelial detachment and necrosis in the pharynx, trachea and bronchioles, while long-term consequences include fibrosis and, in some instances, cancer. Current therapies to treat mustard poisoning are primarily palliative and do not target underlying pathophysiologic mechanisms. New knowledge about vesicant-induced pulmonary disease pathogenesis has led to the identification of potentially efficacious strategies to reduce injury by targeting inflammatory cells and mediators including reactive oxygen and nitrogen species, proteases and proinflammatory/cytotoxic cytokines. Therapeutics under investigation include corticosteroids, N-acetyl cysteine,more » which has both mucolytic and antioxidant properties, inducible nitric oxide synthase inhibitors, liposomes containing superoxide dismutase, catalase, and/or tocopherols, protease inhibitors, and cytokine antagonists such as anti-tumor necrosis factor (TNF)-α antibody and pentoxifylline. Antifibrotic and fibrinolytic treatments may also prove beneficial in ameliorating airway obstruction and lung remodeling. More speculative approaches include inhibitors of transient receptor potential channels, which regulate pulmonary epithelial cell membrane permeability, non-coding RNAs and mesenchymal stem cells. As mustards represent high priority chemical threat agents, identification of effective therapeutics for mitigating toxicity is highly significant.« less

Mustard Vesicant-induced Lung Injury: Advances in Therapy

PubMed Central

Weinberger, Barry; Malaviya, Rama; Sunil, Vasanthi; Venosa, Alessandro; Heck, Diane E.; Laskin, Jeffrey D.; Laskin, Debra L.

2016-01-01

Most mortality and morbidity following exposure to vesicants such as sulfur mustard is due to pulmonary toxicity. Acute injury is characterized by epithelial detachment and necrosis in the pharynx, trachea and bronchioles, while long-term consequences include fibrosis and in some instances, cancer. Current therapies to treat mustard poisoning are primarily palliative and do not target underlying pathophysiologic mechanisms. New knowledge about vesicant-induced pulmonary disease pathogenesis has led to the identification of potentially efficacious strategies to reduce injury by targeting inflammatory cells and mediators including reactive oxygen and nitrogen species, proteases and proinflammatory/cytotoxic cytokines. Therapeutics under investigation include corticosteroids, N-acetyl cysteine, which has both mucolytic and antioxidant properties, inducible nitric oxide synthase inhibitors, liposomes containing superoxide dismutase, catalase, and/or tocopherols, protease inhibitors, and cytokine antagonists such as anti-tumor necrosis factor (TNF)-α antibody and pentoxifylline. Antifibrotic and fibrinolytic treatments may also prove beneficial in ameliorating airway obstruction and lung remodeling. More speculative approaches include inhibitors of transient receptor potential channels, which regulate pulmonary epithelial cell membrane permeability, non-coding RNAs and mesenchymal stem cells. As mustards represent high priority chemical threat agents, identification of effective therapeutics for mitigating toxicity is highly significant. PMID:27212445

Chemotherapy- and radiotherapy-induced oral mucositis: review of preventive strategies and treatment.

PubMed

Saadeh, Claire E

2005-04-01

Oral mucositis is a frequently encountered and potentially severe complication associated with administration of chemotherapy and radiotherapy. Although many pharmacologic interventions have been used for the prevention and treatment of oral mucositis, there is not one universally accepted strategy for its management. Most preventive and treatment strategies are based on limited, often anecdotal, clinical data. Basic oral hygiene and comprehensive patient education are important components of care for any patient with cancer at risk for development of oral mucositis. Nonpharmacologic approaches for the prevention of oral mucositis include oral cryotherapy for patients receiving chemotherapy with bolus 5-fluorouracil, and low-level laser therapy for patients undergoing hematopoietic stem cell transplantation. Chlorhexidine, amifostine, hematologic growth factors, pentoxifylline, glutamine, and several other agents have all been investigated for prevention of oral mucositis. Results have been conflicting, inconclusive, or of limited benefit. Treatment of established mucositis remains a challenge and focuses on a palliative management approach. Topical anesthetics, mixtures (also called cocktails), and mucosal coating agents have been used despite the lack of experimental evidence supporting their efficacy. Investigational agents are targeting the specific mechanisms of mucosal injury; among the most promising of these is recombinant human keratinocyte growth factor.

The Impact of Uterine Radiation on Subsequent Fertility and Pregnancy Outcomes

PubMed Central

Teh, Wan Tinn; Stern, Catharyn; Chander, Sarat; Hickey, Martha

2014-01-01

Future fertility is of paramount importance to younger cancer survivors. Advances in assisted reproductive technology mean that young women treated with radiation involving the uterus may require clinical guidance regarding whether to attempt a pregnancy themselves. We performed a review of the literature regarding radiation involving uterus (total body irradiation (TBI) and pelvic radiation), fertility, and pregnancy outcomes to come up with a recommendation for our patients. Limited evidence suggests lower fecundity and an increased incidence of pregnancy complications after uterine radiation. Higher radiation doses and direct uterine radiation both significantly increase the risk of an adverse pregnancy outcome. Uterine radiation doses of <4 Gy do not appear to impair uterine function. Adult TBI data (usually 12 Gy) suggest pregnancy is possible but with lower fecundity and more complications. Although there is no clear data indicating the dose of radiation to the uterus, above which a pregnancy would not be sustainable, we suggest patients receiving >45 Gy during adulthood and >25 Gy in childhood be counselled to avoid attempting pregnancy. There is preliminary evidence that menopausal hormone therapy and a combination of pentoxifylline and tocopherol may improve uterine function following irradiation. PMID:25165706

Erythema Nodosum Leprosum: Update and challenges on the treatment of a neglected condition.

PubMed

Costa, Perpétua do Socorro Silva; Fraga, Lucas Rosa; Kowalski, Thayne Woycinck; Daxbacher, Egon Luiz Rodrigues; Schuler-Faccini, Lavínia; Vianna, Fernanda Sales Luiz

2018-07-01

Erythema Nodosum Leprosum (ENL) occurs due to the immunological complication of multibacillary leprosy and is characterized by painful nodules and systemic compromising. It is usually recurrent and/or chronic and has both physical and economic impact on the patient, being a very important cause of disability. In addition, ENL is a major health problem in countries where leprosy is endemic. Therefore, adequate control of this condition is important. The management of ENL aims to control acute inflammation and neuritis and prevent the onset of new episodes. However, all currently available treatment modalities have one or two drawbacks and are not effective for all patients. Corticosteroid is the anti-inflammatory of choice in ENL but may cause dependence, especially for chronic patients. Thalidomide has a rapid action but its use is limited due the teratogenicity and neurotoxicity. Clofazimine and pentoxifylline have slow action and have important adverse effects. Finally, there is no pattern or guidelines for treating these patients, becoming more difficult to evaluate and to control this condition. This review aims to show the main drugs used in the treatment of ENL and the challenges in the management of the reaction. Copyright © 2018 Elsevier B.V. All rights reserved.

Effects of Fenton treatment on the properties of effluent organic matter and their relationships with the degradation of pharmaceuticals and personal care products.

PubMed

Li, Wei; Nanaboina, Venkateswarlu; Zhou, Qixing; Korshin, Gregory V

2012-02-01

This study examined effects of Fenton oxidation on trace level pharmaceuticals and personal care products (PPCPs) commonly occurring in wastewater. The tested PPCPs included acetaminophen, atenolol, atrazine, carbamazepine, metoprolol, dilantin, DEET, diclofenac, pentoxifylline, oxybenzone, caffeine, fluoxetine, gemfibrozil, ibuprofen, iopromide, naproxen, propranolol, sulfamethoxazole, bisphenol-A and trimethoprim. Transformations of effluent organic matter (EfOM) caused by Fenton oxidation were also quantified. All tested PPCPs, except atrazine and iopromide, were completely removed by Fenton treatment carried out using a 20mg/L Fe (II) concentration and a 2.5 H(2)O(2)/Fe (II) molar ratio. Up to 30% on the total carbon concentration was removed during Fenton treatment which was accompanied by the oxidation of EfOM molecules and formation of oxidation products such as oxalic, formic and acetic acids and, less prominently, formaldehyde, acetaldehyde, propionaldehyde and glycolaldehyde. The absorbance of EfOM treated with Fenton reagent at varying Fe (II) concentration and contact time underwent a consistent decrease. The relative decrease of EfOM absorbance was strongly and unambiguously correlated with the removal of all tested PPCPs. Copyright © 2011 Elsevier Ltd. All rights reserved.

Medical management of venous ulcers.

PubMed

Pascarella, Luigi; Shortell, Cynthia K

2015-03-01

Venous disease is the most common cause of chronic leg ulceration and represents an advanced clinical manifestation of venous insufficiency. Due to their frequency and chronicity, venous ulcers have a high socioeconomic impact, with treatment costs accounting for 1% of the health care budget in Western countries. The evaluation of patients with venous ulcers should include a thorough medical history for prior deep venous thrombosis, assessment for an hypercoagulable state, and a physical examination. Use of the CEAP (clinical, etiology, anatomy, pathophysiology) Classification System and the revised Venous Clinical Severity Scoring System is strongly recommended to characterize disease severity and assess response to treatment. This venous condition requires lifestyle modification, with affected individuals performing daily intervals of leg elevation to control edema; use of elastic compression garments; and moderate physical activity, such as walking wearing below-knee elastic stockings. Meticulous skin care, treatment of dermatitis, and prompt treatment of cellulitis are important aspects of medical management. The pharmacology of chronic venous insufficiency and venous ulcers include essentially two medications: pentoxifylline and phlebotropic agents. The micronized purified flavonoid fraction is an effective adjunct to compression therapy in patients with large, chronic ulceration. Copyright © 2015 Elsevier Inc. All rights reserved.

Delayed-type hypersensitivity lesions in the central nervous system are prevented by inhibitors of matrix metalloproteinases.

PubMed

Matyszak, M K; Perry, V H

1996-09-01

We have studied the effect of an inhibitor of matrix metalloproleinases, BB-1101, on a delayed-type hypersensitivity (DTH) response in the CNS. We used a recently described model in which heat-killed bacillus Calmette-Guérin (BCG) sequestered behind the blood-brain barrier (BBB) is targeted by a T-cell mediated response after subcutaneous injection of BCG (Matyszak and Perry, 1995). The DTH lesions are characterised by breakdown of the BBB, macrophage and lymphocyte infiltration and tissue damage including myelin loss. Treatment with BB-1101, which is not only a potent inhibitor of matrix metalloproteinases but also strongly inhibits TNF-alpha release, dramatically attenuated the CNS lesions. Breakdown of the BBB and the recruitment of T-cells into the site of the lesion were significantly reduced. There were many fewer inflammatory macrophages in DTH lesions than in comparable lesions from untreated animals. There was also significantly less myelin damage (assessed by staining with anti-MBP antibody). The DTH response in animals treated with dexamethasone was also reduced, but to a lesser degree. No significant effect was seen after administration of pentoxifylline, a phosphodiesterase inhibitor with effects including the inhibition of TNF-alpha production. Our results suggest that inhibitors of matrix metalloproteinases may be of considerable therapeutic benefit in neuroinflammatory diseases.

Impact of different antithrombotics on the microcirculation and viability of perforator-based ischaemic skin flaps in a small animal model.

PubMed

Fichter, Andreas M; Ritschl, Lucas M; Robitzky, Luisa K; Wagenpfeil, Stefan; Mitchell, David A; Wolff, Klaus-Dietrich; Mücke, Thomas

2016-10-21

The effects of antithrombotic drugs on random and free flap survival have been investigated in the past, but the experimental and clinical results are not in agreement. A perforator-based critical ischaemia model was used to evaluate the effects of different perioperatively administered pharmaceutical agents on tissue ischaemia and to assess the potential additional haemorheological or vasodilative effects of antithrombotics on flap microcirculation. Combined laser Doppler flowmetry and remission spectroscopy revealed an increase in certain microcirculation parameters in most groups in comparison with saline controls, and these changes correlated with flap survival. Clopidogrel and hirudin significantly improved the amount of viable flap tissue in comparison with controls, while unfractioned heparin had a negative effect on flap survival. Low molecular weight heparin, aspirin, pentoxifylline, and hydroxyethyl starch had no impact on the amount of viable flap tissue. A higher complication rate was observed in all experimental groups, but only clopidogrel had a negative impact on the flap viability. Our results add to the body of evidence supporting the conclusion that perioperative antithrombotic treatment improves flap survival. Clopidogrel and hirudin are effective pharmacological agents that significantly increased the viability of perforator-based skin flaps in rats, but at a higher risk of postoperative bleeding.

The Influence of High Drug Loading in Xanthan Tablets and Media with Different Physiological pH and Ionic Strength on Swelling and Release.

PubMed

Mikac, Urša; Sepe, Ana; Baumgartner, Saša; Kristl, Julijana

2016-03-07

The formation of a gel coat around xanthan (Xan) tablets, empty or loaded with pentoxifylline (PF), and its release in media differing in pH and ionic strength by NMR, MR imaging, and two release methods were studied. The T1 and T2 NMR relaxation times in gels depend predominantly on Xan concentration; the presence of PF has negligible influence on them. It is interesting that the matrix swelling is primarily regulated by Xan despite high drug loading (25%, 50%). The gastric pH and high ionic strength of the media do not influence the position of the penetration and swelling fronts but do affect the erosion front and gel thickness. The different release profiles obtained in mixing and nonmixing in vitro methods are the consequence of matrix hydration level and erosion at the surface. In water and in diluted acid medium with low ionic strength, the main release mechanism is erosion, whereas in other media (pH 1.2, μ ≥ 0.20 M), anomalous transport dominates as was found out by fitting of measured data with theoretical model. Besides the in vitro investigation that mimics gastric conditions, mathematical modeling makes the product development more successful.

The Anti-Inflammatory Activity of Boron Derivatives in Rodents

PubMed Central

Hall, Iris H.; Burnham, Bruce S.; Chen, Shang Y.; Sood, Anup; Spielvogel, Bernard F.; Morse, Karen W.

1995-01-01

Acyclic amine-carboxyboranes were effective anti-inflammatory agents in mice at 8 mg/kg x 2. These amine-carboxyboranes were more effective than the standard indomethacin at 8 mg/kg x 2, pentoxifylline at 50 mg/kg x 2, and phenylbutazone at 50 mg/kg x 2. The heterocyclic amine derivatives as well as amine-carbamoylboranes, carboalkoxyboranes, and cyanoboranes were generally less active. However, selected aminomethyl-phosphonate-N-cyanoboranes demonstrated greater than 60% reduction of induced inflammation. The boron compounds were also active in the rat induced edema, chronic arthritis, and pleurisy screens, demonstrating activity similar to the standard indomethacin. The compounds were effecive in reducing local pain and decreased the tail flick reflex to pain. The derivatives which demonstrated good anti-inflammatory activity were effective inhibitors of hydrolytic lysosomal, and proteolytic enzyme activities with IC50 50 values equal to -6M in mouse macrophages, human leukocytes, and Be Sal osteofibrolytic cells. In these same cell lines, the agents blocked prostaglandin cyclooxygenase activity with IC50 values of -6M. In mouse macrophage and human leukocytes, 5′ lipoxygenase activity was also inhibited by the boron derivatives with IC50 values of 10-6M. These IC50 values for inhibition of these enzyme activities are consistent with published values of known anti-inflammatory agents which target these enzymes. PMID:18472741

Novel Indications for Commonly Used Medications as Radiation Protectants in Spaceflight.

PubMed

McLaughlin, Mark F; Donoviel, Dorit B; Jones, Jeffrey A

2017-07-01

In the space environment, the traditional radioprotective principles of time, distance, and shielding become difficult to implement. Additionally, the complex radiation environment inherent in space, the chronic exposure timeframe, and the presence of numerous confounding variables complicate the process of creating appropriate risk models for astronaut exposure. Pharmaceutical options hold tremendous promise to attenuate acute and late effects of radiation exposure in the astronaut population. Pharmaceuticals currently approved for other indications may also offer radiation protection, modulation, or mitigation properties along with a well-established safety profile. Currently there are only three agents which have been clinically approved to be employed for radiation exposure, and these only for very narrow indications. This review identifies a number of agents currently approved by the U.S. Food and Drug Administration (FDA) which could warrant further investigation for use in astronauts. Specifically, we examine preclinical and clinical evidence for statins, nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), metformin, calcium channel blockers, β adrenergic receptor blockers, fingolimod, N-acetylcysteine, and pentoxifylline as potential radiation countermeasures.McLaughlin MF, Donoviel DB, Jones JA. Novel indications for commonly used medications as radiation protectants in spaceflight. Aerosp Med Hum Perform. 2017; 88(7):665-676.

Improvements in the Management of Diabetic Nephropathy

PubMed Central

Dounousi, Evangelia; Duni, Anila; Leivaditis, Konstantinos; Vaios, Vasilios; Eleftheriadis, Theodoros; Liakopoulos, Vassilios

2015-01-01

The burden of diabetes mellitus is relentlessly increasing. Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) worldwide and a major cause of morbidity and mortality in patients with diabetes. The current standard therapy of diabetic nephropathy involves intensive treatment of hyperglycemia and strict blood pressure control, mainly via blockade of the renin-angiotensin system (RAS). Attention has been drawn to additional beneficial effects of oral hypoglycemic drugs and fibrates on other aspects of diabetic nephropathy. On the other hand, antiproteinuric effects of RAS combination therapy do not seem to enhance the prevention of renal disease progression, and it has been associated with an increased rate of serious adverse events. Novel agents, such as bardoxolone methyl, pentoxifylline, inhibitors of protein kinase C (PKC), sulodexide, pirfenidone, endothelin receptor antagonists, vitamin D supplements, and phosphate binders have been associated with controversial outcomes or significant side effects. Although new insights into the pathogenetic mechanisms have opened new horizons towards novel interventions, there is still a long way to go in the field of DN research. The aim of this review is to highlight the recent progress made in the field of diabetes management based on the existing evidence. The article also discusses novel targets of therapy, with a special focus on the major pathophysiologic mechanisms implicated in the initiation and progression of diabetic nephropathy. PMID:26676665

Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury.

PubMed

Llacuna, Laura; Marí, Montserrat; Garcia-Ruiz, Carmen; Fernandez-Checa, José C; Morales, Albert

2006-09-01

The molecular mechanisms of hepatic ischemia/reperfusion (I/R) damage are incompletely understood. We investigated the role of ceramide in a murine model of warm hepatic I/R injury. This sphingolipid induces cell death and participates in tumor necrosis factor (TNF) signaling. Hepatic ceramide levels transiently increased after the reperfusion phase of the ischemic liver in mice, because of an early activation of acidic sphingomyelinase (ASMase) followed by acid ceramidase stimulation. In vivo administration of an ASMase inhibitor, imipramine, or ASMase knockdown by siRNA decreased ceramide generation during I/R, and attenuated serum ALT levels, hepatocellular necrosis, cytochrome c release, and caspase-3 activation. ASMase-induced ceramide generation activated JNK resulting in BimL phosphorylation and translocation to mitochondria, as the inhibition of ASMase by imipramine prevented these events. In contrast, blockade of ceramide catabolism by N-oleyolethanolamine (NOE), a ceramidase inhibitor, enhanced ceramide levels and potentiated I/R injury compared with vehicle-treated mice. Pentoxifylline treatment prevented TNF upregulation and ASMase activation. Furthermore, 9 of 11 mice treated with imipramine survived 7 days after total liver ischemia, compared with 4 of 12 vehicle-treated mice, whereas 8 of 8 NOE-treated mice died within 2 days of total liver ischemia. In conclusion, ceramide generated from ASMase plays a key role in I/R-induced liver damage, and its modulation may be of therapeutic relevance.

Inhibition of plasma lipid oxidation induced by peroxyl radicals, peroxynitrite, hypochlorite, 15-lipoxygenase, and singlet oxygen by clinical drugs.

PubMed

Morita, Mayuko; Naito, Yuji; Yoshikawa, Toshikazu; Niki, Etsuo

2016-11-15

With increasing evidence showing the involvement of oxidative stress in the pathogenesis of various diseases, the effects of clinical drugs possessing antioxidant functions have received much attention. The unregulated oxidative modification of biological molecules leading to diseases is mediated by multiple oxidants including free radicals, peroxynitrite, hypochlorite, lipoxygenase, and singlet oxygen. The capacity of antioxidants to scavenge or quench oxidants depends on the nature of oxidants. In the present study, the antioxidant effects of several clinical drugs against plasma lipid oxidation induced by the aforementioned five kinds of oxidants were investigated from the production of lipid hydroperoxides, which have been implicated in the pathogenesis of various diseases. Troglitazone acted as a potent peroxyl radical scavenger, whereas probucol and edaravone showed only moderate reactivity and carvedilol, pentoxifylline, and ebselen did not act as radical scavenger. Probucol and edaravone suppressed plasma oxidation mediated by peroxynitrite and hypochlorite. Troglitazone and edaravone inhibited 15-lipoxygenase mediated plasma lipid oxidation, the IC 50 being 20 and 34μM respectively. None of the drugs used in this study suppressed plasma lipid oxidation by singlet oxygen. This study shows that the antioxidant effects of drugs depend on the nature of oxidants and that antioxidants against multiple oxidants are required to cope with oxidative stress in vivo. Copyright © 2016 Elsevier Ltd. All rights reserved.

Gateways to Clinical Trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2002-09-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Adalimumab, aeroDose insulin inhaler, agomelatine, alendronic acid sodium salt, aliskiren fumarate, alteplase, amlodipine, aspirin, atazanavir; Bacillus Calmette-Guérin, basiliximab, BQ-788, bupropion hydrochloride; Cabergoline, caffeine citrate, carbamazepine, carvedilol, celecoxib, cyclosporine, clopidogrel hydrogensulfate, colestyramine; Dexamethasone, diclofenac sodium, digoxin, dipyridamole, docetaxel, dutasteride; Eletriptan, enfuvirtidie, eplerenone, ergotamine tartrate, esomeprazole magnesium, estramustine phosphate sodium; Finasteride, fluticasone propionate, fosinopril sodium; Ganciclovir, GBE-761-ONC, glatiramer acetate, gliclazide, granulocyte-CSF; Heparin sodium, human isophane insulin (pyr), Hydrochlorothiazide; Ibuprofen, inhaled insulin, interferon alfa, interferon beta-1a; Laminvudine, lansoprazole, lisinopril, lonafarnib, losartan potassium, lumiracoxib; MAb G250, meloxicam methotrexate, methylprednisolone aceponate, mitomycin, mycophenolate mofetil; Naproxen sodium, natalizumab, nelfinavir mesilate, nemifitide ditriflutate, nimesulide; Omalizumab, omapatrilat, omeprazole, oxybutynin chloride; Pantoprazole sodium, paracetamol, paroxetine, pentoxifylline, pergolide mesylate, permixon, phVEGF-A165, pramipexole hydrochloride, prasterone, prednisone, probucol, propiverine hydrochloride; Rabeprazole sodium, resiniferatoxin, risedronate sodium, risperidone, rofecoxib rosiglitazone maleate, ruboxistaurin mesilate hydrate; Selegiline transdermal system, sertraline, sildenafil citrate, streptokinase; Tadalafil, tamsulosin hydrochloride, technosphere/Insulin, tegaserod maleate, tenofovir disoproxil fumarate, testosterone heptanoate, testosterone undecanoate, tipifarnib, tolterodine tartrate, topiramate, troglitazone; Ursodeoxycholic acid; Valdecoxib, valsartan, vardenafil, venlafaxine hydrochloride, VX-745.

Effects of combination of aliskiren and pentoxyfylline on renal function in the rat remnant kidney model of chronic renal failure.

PubMed

Soni, Hitesh M; Patel, Praful P; Patel, Savan; Rath, Akshyaya C; Acharya, Aviseka; Trivedi, Harshkant D; Jain, Mukul R

2015-01-01

The aim was to investigate the nephroprotective effect of combination of aliskiren (ASK), a direct renin inhibitor and pentoxifylline (PTX), inhibitor of tumor necrotic factor-alpha (TNF-alpha), in rat remnant kidney model of chronic kidney disease (CKD). Nephrectomized (NPX) rats were treated with ASK (10 mg/kg, p.o.), PTX (100 mg/kg, p.o.), and combination of PTX + ASK once daily for 28 days. We have performed analysis of various renal injury parameters after 4 weeks of treatment. Treatment with PTX, ASK and combination showed significant improvement in urea, creatinine and total protein in plasma when compared with vehicle treated group in NPX rats. ASK and combination of PTX + ASK elicited significant reduction in blood pressure but PTX alone did not produce blood pressure reduction. ASK treatment showed significant elevation in TNF-alpha, whereas PTX and ASK + PTX showed significant reduction in TNF-alpha in plasma. Histopathologically, the extent of the kidney injury was similar in NPX + vehicle and NPX + ASK-treated rats. PTX and ASK + PTX-treated group showed lesser extent of kidney injury. There was good correlation of mRNA expression levels of kidney injury molecule-1 and bradykinin B1 receptor data with histopathological findings in kidney samples and elevated TNF-alpha levels in plasma. We conclude that combination of PTX + ASK may be better therapeutic intervention for nephroprotection in CKD patients.

Biodegradation of pharmaceuticals and endocrine disruptors with oxygen, nitrate, manganese (IV), iron (III) and sulfate as electron acceptors

NASA Astrophysics Data System (ADS)

Schmidt, Natalie; Page, Declan; Tiehm, Andreas

2017-08-01

Biodegradation of pharmaceuticals and endocrine disrupting compounds was examined in long term batch experiments for a period of two and a half years to obtain more insight into the effects of redox conditions. A mix including lipid lowering agents (e.g. clofibric acid, gemfibrozil), analgesics (e.g. diclofenac, naproxen), beta blockers (e.g. atenolol, propranolol), X-ray contrast media (e.g. diatrizoic acid, iomeprol) as well as the antiepileptic carbamazepine and endocrine disruptors (e.g. bisphenol A, 17α-ethinylestradiol) was analyzed in batch tests in the presence of oxygen, nitrate, manganese (IV), iron (III), and sulfate. Out of the 23 selected substances, 14 showed a degradation of > 50% of their initial concentrations under aerobic conditions. The beta blockers propranolol and atenolol and the analgesics pentoxifylline and naproxen showed a removal of > 50% under anaerobic conditions. In particular naproxen proved to be degradable with oxygen and under most anaerobic conditions, i.e. with manganese (IV), iron (III), or sulfate. The natural estrogens estriol, estrone and 17β-estradiol showed complete biodegradation under aerobic and nitrate-reducing conditions, with a temporary increase of estrone during transformation of estriol and 17β-estradiol. Transformation of 17β-estradiol under Fe(III)-reducing conditions resulted in an increase of estriol as well. Concentrations of clofibric acid, carbamazepine, iopamidol and diatrizoic acid, known for their recalcitrance in the environment, remained unchanged.

[Latest advances in acute pancreatitis].

PubMed

de-Madaria, Enrique

2013-10-01

The present article analyzes the main presentations on acute pancreatitis (AP) in Digestive Disease Week 2013. Perfusion computed tomography allows early diagnosis of pancreatic necrosis. Neutrophil gelatinase-associated lipocalin predicts the development of acute renal failure, severe AP and death. Factors associated with greater fluid sequestration in AP are alcoholic etiology, an elevated hematocrit, and the presence of criteria of systemic inflammatory response syndrome; fluid sequestration is associated with a worse outcome. True pseudocysts (fluid collections without necrosis for more than 4 weeks) are a highly infrequent complication in AP. Patients with necrotic collections have a poor prognosis, especially if associated with infection. A meta-analysis on fluid therapy suggests that early aggressive fluid administration is associated with higher mortality and more frequent respiratory complications. According to a meta-analysis, enteral nutrition initiated within 24 hours of admission improves the outcome of AP compared with later initiation of enteral nutrition. Pentoxifylline could be a promising alternative in AP; a double-blind randomized study showed that this drug reduced the length of hospital and intensive care unit stay, as well as the need for intensive care unit admission. The association of octreotide and celecoxib seems to reduce the frequency of organ damage compared with octreotide alone. Mild AP can be managed in the ambulatory setting through hospital-at-home units after a short, 24-hour admission. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Biodegradation of pharmaceuticals and endocrine disruptors with oxygen, nitrate, manganese (IV), iron (III) and sulfate as electron acceptors.

PubMed

Schmidt, Natalie; Page, Declan; Tiehm, Andreas

2017-08-01

Biodegradation of pharmaceuticals and endocrine disrupting compounds was examined in long term batch experiments for a period of two and a half years to obtain more insight into the effects of redox conditions. A mix including lipid lowering agents (e.g. clofibric acid, gemfibrozil), analgesics (e.g. diclofenac, naproxen), beta blockers (e.g. atenolol, propranolol), X-ray contrast media (e.g. diatrizoic acid, iomeprol) as well as the antiepileptic carbamazepine and endocrine disruptors (e.g. bisphenol A, 17α-ethinylestradiol) was analyzed in batch tests in the presence of oxygen, nitrate, manganese (IV), iron (III), and sulfate. Out of the 23 selected substances, 14 showed a degradation of >50% of their initial concentrations under aerobic conditions. The beta blockers propranolol and atenolol and the analgesics pentoxifylline and naproxen showed a removal of >50% under anaerobic conditions. In particular naproxen proved to be degradable with oxygen and under most anaerobic conditions, i.e. with manganese (IV), iron (III), or sulfate. The natural estrogens estriol, estrone and 17β-estradiol showed complete biodegradation under aerobic and nitrate-reducing conditions, with a temporary increase of estrone during transformation of estriol and 17β-estradiol. Transformation of 17β-estradiol under Fe(III)-reducing conditions resulted in an increase of estriol as well. Concentrations of clofibric acid, carbamazepine, iopamidol and diatrizoic acid, known for their recalcitrance in the environment, remained unchanged. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Targeting inflammation in diabetes: Newer therapeutic options

PubMed Central

Agrawal, Neeraj Kumar; Kant, Saket

2014-01-01

Inflammation has been recognised to both decrease beta cell insulin secretion and increase insulin resistance. Circulating cytokines can affect beta cell function directly leading to secretory dysfunction and increased apoptosis. These cytokines can also indirectly affect beta cell function by increasing adipocyte inflammation.The resulting glucotoxicity and lipotoxicity further enhance the inflammatory process resulting in a vicious cycle. Weight reduction and drugs such as metformin have been shown to decrease the levels of C-Reactive Protein by 31% and 13%, respectively. Pioglitazone, insulin and statins have anti-inflammatory effects. Interleukin 1 and tumor necrosis factor-α antagonists are in trials and NSAIDs such as salsalate have shown an improvement in insulin sensitivity. Inhibition of 12-lipo-oxygenase, histone de-acetylases, and activation of sirtuin-1 are upcoming molecular targets to reduce inflammation. These therapies have also been shown to decrease the conversion of pre-diabetes state to diabetes. Drugs like glicazide, troglitazone, N-acetylcysteine and selective COX-2 inhibitors have shown benefit in diabetic neuropathy by decreasing inflammatory markers. Retinopathy drugs are used to target vascular endothelial growth factor, angiopoietin-2, various proteinases and chemokines. Drugs targeting the proteinases and various chemokines are pentoxifylline, inhibitors of nuclear factor-kappa B and mammalian target of rapamycin and are in clinical trials for diabetic nephropathy. Commonly used drugs such as insulin, metformin, peroxisome proliferator-activated receptors, glucagon like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors also decrease inflammation. Anti-inflammatory therapies represent a potential approach for the therapy of diabetes and its complications. PMID:25317247

The Study of Pentoxifylline Drug Effects on Renal Apoptosis and BCL-2 Gene Expression Changes Following Ischemic Reperfusion Injury in Rat

PubMed Central

Hashemi, Mehrdad

2014-01-01

Ischemia Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. In this study, the effect of pentoxyfylline on BCL-2 gene expression changes and cell injury in kidney of rat following Ischemia Reperfusion were evaluated. In this experimental study, 20 male wistar rats with average weight of 250-300 g were selected and then were accidently divided them on two tenth group of control and treatment groups. In the control group, celiotomy was performed by ventral midline incision. The left kidney was isolated, and then both the renal artery and vein were obstructed. After 60 minutes of warm ischemia, vessel obstruction resolved and the right kidney was removed. 72 hours after reperfusion, tissue samples were taken from left kidney for Tunel assay. We used quantitative real time PCR for detection of BCL-2 gene expression in treated groups and then compared them to control samples. In the treatment group, the cell death changes, showed lower level than the control group. The results also showed the BCL-2 gene expression was declined in ischemia group as campared to PNT drug group. The pentoxyfylline might have a role in control of apoptosis result from Ischemia- reperfusion and quantitative real-time PCR can be used as a direct method for detection BCL-2 gene expression in tested samples and normal samples. PMID:24734070

Persistent Interictal Musical Hallucination in a Patient With Mesial Temporal Sclerosis-Related Epilepsy: First Case Report and Etiopathological Hypothesis.

PubMed

Borelli, Paolo; Vedovello, Marcella; Braga, Massimiliano; Pederzoli, Massimo; Beretta, Sandro

2016-12-01

Musical hallucination is a disorder of complex sound processing of instrumental music, songs, choirs, chants, etc. The underlying pathologies include moderate to severe acquired hearing loss (the auditory equivalent of Charles Bonnet syndrome), psychiatric illnesses (depression, schizophrenia), drug intoxication (benzodiazepines, salicylate, pentoxifylline, propranolol), traumatic lesions along the acoustic pathways, and epilepsy. The hallucinations are most likely to begin late in life; 70% of patients are women. Musical hallucination has no known specific therapy. Treating the underlying cause is the most effective approach; neuroleptic and antidepressant medications have only rarely succeeded.Musical hallucination in epilepsy typically presents as simple partial seizures originating in the lateral temporal cortex. To our knowledge, no formal report of musical hallucination in the interictal state has been published before. In contrast, other interictal psychotic features are a relatively common complication, especially in patients with long-standing drug-resistant epilepsy.We describe a 62-year-old woman with a long history of mesial temporal lobe epilepsy whose musical hallucination was solely interictal. We speculate on the possible link between temporal epilepsy and her hallucination. We hypothesize that, as a result of her epileptic activity-induced damage, an imbalance developed between the excitatory and inhibitory projections connecting the mesial temporal cortex to the other auditory structures. These structures may have generated hyperactivity in the lateral temporal cortex through a "release" mechanism that eventually resulted in musical hallucination.

A Systematic Review of Topical Vasodilators for the Treatment of Intraoperative Vasospasm in Reconstructive Microsurgery.

PubMed

Vargas, Christina R; Iorio, Matthew L; Lee, Bernard T

2015-08-01

Intraoperative vasospasm during reconstructive microsurgery is common, often unpredictable, and potentially devastating with regard to flap survival. Current methods of pharmacologic management vary, and may be shifting as a result of changes in the availability of individual medications. This review aims to provide a concise examination of the published literature regarding use, efficacy, and adverse effects of the agents described for local management of vascular spasm during microsurgery. A systematic review of the literature was performed to identify articles relevant to pharmacologic treatment of intraoperative vasospasm in vivo. An additional review of the literature was performed with regard to each agent identified in order to provide clinical background information. Systematic review identified 20 articles, in which 14 vasodilator agents were evaluated. Drugs were classified into five pharmacologic categories: phosphodiesterase inhibitors (papaverine, pentoxifylline, and amrinone), local anesthetics (lidocaine), calcium channel blockers (nicardipine, verapamil, nifedipine, and magnesium sulfate), direct vasodilators (sodium nitroprusside, prostaglandin E1, nitroglycerin, and hydralazine), and alpha antagonists (phentolamine and chlorpromazine). Despite a variety of methods, these studies indicate some degree of experimental evidence of efficacy for each of these agents. Available literature regarding use of topical vasodilating agents for intraoperative management of vasospasm during microsurgery is limited and largely based on animal models, which may not reliably generalize to the reconstructive patient population. Well-controlled translational study in clinically applicable and reproducible models is needed to guide evidence-based clinical management of this important phenomenon.

Management practices of hepatitis C virus infected alcoholic hepatitis patients: A survey of physicians.

PubMed

Singal, Ashwani K; Salameh, Habeeb; Singal, Anjna; Jampana, Sarat C; Freeman, Daniel H; Anderson, Karl E; Brunder, Don

2013-05-06

To survey gastroenterologists and hepatologists regarding their current views on treating hepatitis C virus (HCV) infected alcoholic hepatitis (AH) patients. A sixteen item questionnaire was electronically mailed to gastroenterologists and hepatologists. A reminder was sent after 2 mo to increase the response rate. Participation of respondents was confidential. Accessing secured web site to respond to the questionnaire was considered as informed consent. Responses received on the secured website were downloaded in an excel sheet for data analysis. Analyzing 416 responses to 1556 (27% response rate) emails, 57% respondents (56% gastroenterologists) reported HCV prevalence > 20% amongst AH patients. Sixty nine percent often treated AH and 46% preferred corticosteroids (CS). Proportion of respondents with consensus (75% or more respondents agreeing on question) on specific management of HCV infected AH were: routine HCV testing (94%), HCV not changing response to CS (80%) or pentoxifylline (91%), no change in approach to treating HCV infected AH (75%). None of respondent variables: age, specialty, annual number of patients seen, and HCV prevalence could predict respondent to be in consensus on any of or all 4 questions. Further, only 4% would choose CS for treating HCV infected AH as opposed to 47% while treating HCV negative AH. Gastroenterologists and hepatologists believe that AH patients be routinely checked for HCV. However, there is lack of consensus on choice of drug for treatment and outcome of HCV positive AH patients. Studies are needed to develop guidelines for management of HCV infected AH patients.

Inhibitory effect of troglitazone on diabetic neuropathy in streptozotocin-induced diabetic rats.

PubMed

Qiang, X; Satoh, J; Sagara, M; Fukuzawa, M; Masuda, T; Sakata, Y; Muto, G; Muto, Y; Takahashi, K; Toyota, T

1998-11-01

Free-radical scavengers and inhibitors of tumour necrosis factor-alpha (TNF-alpha) such as N-acetylcysteine and pentoxifylline have been shown to inhibit the development of peripheral neuropathy in streptozotocin(STZ)-induced diabetic rats. In this study we examined the effect of troglitazone, an anti-diabetic thiazolidinedione, on diabetic neuropathy, since it also is a free-radical scavenger and a TNF-alpha inhibitor. Rats were fed powder chow mixed with troglitazone at 0.5% and 0.125% ad libitum. Although blood glucose concentrations were remarkably higher and body weight lower in diabetic than in nondiabetic rats, troglitazone had no effect on these throughout the 24-week experiment. Serum lipoperoxide concentrations, tibial nerve lipoperoxide content and serum TNF-alpha activity induced by lipopolysaccharide was increased in diabetic rats, but inhibited in troglitazone-treated rats. Motor nerve conduction velocity (MNCV) of the tibial nerve slowed in diabetic rats, compared with that in nondiabetic rats. On the other hand, the slowed MNCV was (p < 0.05-0.01) inhibited after weeks 12 and 16 of the experiment in diabetic rats treated with high and low doses of troglitazone, respectively. Morphometric analysis showed that troglitazone suppressed the decrease of the myelinated fibre area (p < 0.05), axon/myelin ratio (p < 0.01) and fascicular area (p < 0.05) and suppressed the increase of myelinated fibre density (p < 0.001) in diabetic rats. These results indicate that troglitazone has a beneficial effect on peripheral neuropathy in STZ-induced diabetic rats irrespective of blood glucose concentrations.

Gliclazide inhibits diabetic neuropathy irrespective of blood glucose levels in streptozotocin-induced diabetic rats.

PubMed

Qiang, X; Satoh, J; Sagara, M; Fukuzawa, M; Masuda, T; Miyaguchi, S; Takahashi, K; Toyota, T

1998-08-01

N-acetylcysteine and pentoxifylline, free radical scavengers and inhibitors of tumor necrosis factor-alpha (TNF-alpha) production, inhibit the development of peripheral neuropathy in streptozotocin (STZ)-induced diabetic rats. This study was designed to elucidate the effect of gliclazide, an oral hypoglycemic sulfonylurea, on diabetic neuropathy, because it has been indicated to be a free radical scavenger and TNF-alpha inhibitor. Rats were fed with powder chow mixed with gliclazide or glibenclamide as a control ad libitum. Blood glucose levels and body weight were remarkably higher and lower in diabetic than in nondiabetic rats, respectively, while gliclazide and glibenclamide had no effect on these in both diabetic and nondiabetic rats throughout a 24-week experiment. Serum lipoperoxide levels and lipopolysaccharide (LPS)-induced serum TNF-alpha activities were significantly increased in diabetic rats, whereas these were significantly inhibited in gliclazide-treated rats. Motor nerve conduction velocity (MNCV) of the tibial nerve significantly slowed in diabetic rats compared with nondiabetic rats. On the other hand, the slowed MNCV was significantly inhibited in gliclazide-treated diabetic rats after 16 experimental weeks. Morphometric analysis showed that gliclazide prevented decreased myelinated fiber area (P < .05), increased fiber density (P < .001), and decreased axon/myelin ratio (P < .05) in diabetic rats. Glibenclamide treatment did not affect serum lipoperoxide, TNF-alpha, MNCV, or nerve morphology in this experiment. These results indicate that gliclazide has a beneficial effect on peripheral neuropathy in STZ-induced diabetic rats, irrespective of blood glucose levels.

The effect of pharmacological treatment on gait biomechanics in peripheral arterial disease patients

PubMed Central

2010-01-01

Background Pharmacological treatment has been advocated as a first line therapy for Peripheral Arterial Disease (PAD) patients suffering from intermittent claudication. Previous studies document the ability of pharmacological treatment to increase walking distances. However, the effect of pharmacological treatment on gait biomechanics in PAD patients has not been objectively evaluated as is common with other gait abnormalities. Methods Sixteen patients were prescribed an FDA approved drug (Pentoxifylline or Cilostazol) for the treatment of symptomatic PAD. Patients underwent baseline gait testing prior to medication use which consisted of acquisition of ground reaction forces and kinematics while walking in a pain free state. After three months of treatment, patients underwent repeat gait testing. Results Patients with symptomatic PAD had significant gait abnormalities at baseline during pain free walking as compared to healthy controls. However, pharmacological treatment did not produce any identifiable alterations on the biomechanics of gait of the PAD patients as revealed by the statistical comparisons performed between pre and post-treatment and between post-treatment and the healthy controls. Conclusions Pharmacological treatment did not result in statistically significant improvements in the gait biomechanics of patients with symptomatic PAD. Future studies will need to further explore different cohorts of patients that have shown to improve significantly their claudication distances and/or their muscle fiber morphology with the use of pharmacological treatment and determine if this is associated with an improvement in gait biomechanics. Using these methods we may distinguish the patients who benefit from pharmacotherapy and those who do not. PMID:20529284

Treatment of Cachexia in Oncology

PubMed Central

Tazi, EM; Errihani, H

2010-01-01

Cachexia is a complex metabolic syndrome associated with many chronic or end-stage diseases, especially cancer, and is characterized by loss of muscle with or without loss of fat mass. The management of cachexia is a complex challenge that should address the different causes underlying this clinical event with an integrated or multimodal treatment approach targeting the different factors involved in its pathophysiology. The purpose of this article was to review the current medical treatment of cancer-related cachexia, in particular focusing on combination therapy and ongoing research. Among the treatments proposed in the literature for cancer-related cachexia, some proved to be ineffective, namely, cyproheptadine, hydrazine, metoclopramide, and pentoxifylline. Among effective treatments, progestagens are currently considered the best available treatment option for cancer-related cachexia, and they are the only drugs approved in Europe. Drugs with a strong rationale that have failed or have not shown univocal results in clinical trials so far include eicosapentaenoic acid, cannabinoids, bortezomib, and anti-TNF-alpha MoAb. Several emerging drugs have shown promising results but are still under clinical investigation (thalidomide, selective cox-2 inhibitors, ghrelin mimetics, insulin, oxandrolone, and olanzapine). To date, despite several years of coordinated efforts in basic and clinical research, practice guidelines for the prevention and treatment of cancer-related muscle wasting are lacking, mainly because of the multifactorial pathogenesis of the syndrome. From all the data presented, one can speculate that one single therapy may not be completely successful in the treatment of cachexia. From this point of view, treatments involving different combinations are more likely to be successful. PMID:21218002

A taurine-supplemented vegan diet may blunt the contribution of neutrophil activation to acute coronary events.

PubMed

McCarty, Mark F

2004-01-01

Neutrophils are activated in the coronary circulation during acute coronary events (unstable angina and myocardial infarction), often prior to the onset of ischemic damage. Moreover, neutrophils infiltrate coronary plaque in these circumstances, and may contribute to the rupture or erosion of this plaque, triggering thrombosis. Activated neutrophils secrete proteolytic enzymes in latent forms which are activated by the hypochlorous acid (HOCl) generated by myeloperoxidase. These phenomena may help to explain why an elevated white cell count has been found to be an independent coronary risk factor. Low-fat vegan diets can decrease circulating leukocytes--neutrophils and monocytes--possibly owing to down-regulation of systemic IGF-I activity. Thus, a relative neutropenia may contribute to the coronary protection afforded by such diets. However, vegetarian diets are devoid of taurine - the physiological antagonist of HOCl--and tissue levels of this nutrient are relatively low in vegetarians. Taurine has anti-atherosclerotic activity in animal models, possibly reflecting a role for macrophage-derived myeloperoxidase in the atherogenic process. Taurine also has platelet-stabilizing and anti-hypertensive effects that presumably could reduce coronary risk. Thus, it is proposed that a taurine-supplemented low-fat vegan diet represents a rational strategy for diminishing the contribution of activated neutrophils to acute coronary events; moreover, such a regimen would work in a number of other complementary ways to promote cardiovascular health. Moderate alcohol consumption, the well-tolerated drug pentoxifylline, and 5-lipoxygenase inhibitors--zileuton, boswellic acids, fish oil--may also have potential in this regard. Copyright 2004 Elsevier Ltd.

Diagnosis and Management of Alcoholic Liver Disease.

PubMed

Dugum, Mohannad; McCullough, Arthur

2015-06-28

Alcohol is a leading cause of liver disease and is associated with significant morbidity and mortality. Several factors, including the amount and duration of alcohol consumption, affect the development and progression of alcoholic liver disease (ALD). ALD represents a spectrum of liver pathology ranging from fatty change to fibrosis to cirrhosis. Early diagnosis of ALD is important to encourage alcohol abstinence, minimize the progression of liver fibrosis, and manage cirrhosis-related complications including hepatocellular carcinoma. A number of questionnaires and laboratory tests are available to screen for alcohol intake. Liver biopsy remains the gold-standard diagnostic tool for ALD, but noninvasive accurate alternatives, including a number of biochemical tests as well as liver stiffness measurement, are increasingly being utilized in the evaluation of patients with suspected ALD. The management of ALD depends largely on complete abstinence from alcohol. Supportive care should focus on treating alcohol withdrawal and providing enteral nutrition while managing the complications of liver failure. Alcoholic hepatitis (AH) is a devastating acute form of ALD that requires early recognition and specialized tertiary medical care. Assessment of AH severity using defined scoring systems is important to allocate resources and initiate appropriate therapy. Corticosteroids or pentoxifylline are commonly used in treating AH but provide a limited survival benefit. Liver transplantation represents the ultimate therapy for patients with alcoholic cirrhosis, with most transplant centers mandating a 6 month period of abstinence from alcohol before listing. Early liver transplantation is also emerging as a therapeutic measure in specifically selected patients with severe AH. A number of novel targeted therapies for ALD are currently being evaluated in clinical trials.

Autism, an extreme challenge to integrative medicine. Part 2: medical management.

PubMed

Kidd, Parris M

2002-12-01

Autism and allied autistic spectrum disorders (ASD) present myriad behavioral, clinical, and biochemical abnormalities. Parental participation, advanced testing protocols, and eclectic treatment strategies have driven progress toward cure. Behavioral modification and structured education are beneficial but insufficient. Dietary restrictions, including removal of milk and other casein dairy products, wheat and other gluten sources, sugar, chocolate, preservatives, and food coloring are beneficial and prerequisite to benefit from other interventions. Individualized IgG or IgE testing can identify other troublesome foods but not non-immune mediated food sensitivities. Gastrointestinal improvement rests on controlling Candida and other parasites, and using probiotic bacteria and nutrients to correct dysbiosis and decrease gut permeability. Detoxification of mercury and other heavy metals by DMSA/DMPS chelation can have marked benefit. Documented sulfoxidation-sulfation inadequacies call for sulfur-sulfhydryl repletion and other liver p450 support. Many nutrient supplements are beneficial and well tolerated, including dimethylglycine (DMG) and a combination of pyridoxine (vitamin B6) and magnesium, both of which benefit roughly half of ASD cases. Vitamins A, B3, C, and folic acid; the minerals calcium and zinc; cod liver oil; and digestive enzymes, all offer benefit. Secretin, a triggering factor for digestion, is presently under investigation. Immune therapies (pentoxifyllin, intravenous immunoglobulin, transfer factor, and colostrum) benefit selected cases. Long-chain omega-3 fatty acids offer great promise. Current pharmaceuticals fail to benefit the primary symptoms and can have marked adverse effects. Individualized, in-depth clinical and laboratory assessments and integrative parent-physician-scientist cooperation are the keys to successful ASD management.

Burns, inflammation, and intestinal injury: protective effects of an anti-inflammatory resuscitation strategy.

PubMed

Costantini, Todd W; Peterson, Carrie Y; Kroll, Lauren; Loomis, William H; Putnam, James G; Wolf, Paul; Eliceiri, Brian P; Baird, Andrew; Bansal, Vishal; Coimbra, Raul

2009-12-01

Intestinal barrier breakdown after severe burn can lead to intestinal inflammation, which may act as the source of the systemic inflammatory response. In vitro intestinal cell studies have shown that mitogen-activated protein kinase (MAPK) signaling is an important modulator of intestinal inflammation. We have previously observed that pentoxifylline (PTX) attenuates burn-induced intestinal permeability and tight junction breakdown. We hypothesized that PTX would limit intestinal barrier breakdown and attenuate inflammatory signaling via the MAPK pathway. Male balb/c mice underwent 30% total body surface area full-thickness steam burn. Immediately after burn, animals received an intraperitoneal injection of PTX (12.5 mg/kg) in normal saline or normal saline alone. In vivo intestinal permeability to 4 kDa fluorescein isothiocyanate-dextran was measured. Intestinal extracts were obtained to measure interleukin-6 by enzyme-linked immunosorbent assay, and phosphorylated p38 MAPK, p38 MAPK, phosphorylated extracellular signal-related kinase (1/2) (ERK (1/2)), and ERK (1/2) by immunoblotting. Acute lung injury was assessed by histology at 24 hours after burn. Administration of PTX immediately after injury attenuated burn-induced intestinal permeability. PTX also decreased the burn-induced phosphorylation of p38 MAPK and decreased phosphorylation of ERK (1/2) at 2 hours and 24 hours after injury. Animals given PTX had decreased intestinal interleukin-6 levels. A single dose of PTX also decreased histologic lung injury at 24 hours after burn. PTX attenuates burn-induced intestinal permeability and subsequent intestinal inflammation. Use of PTX after burn was also associated with decreased acute lung injury. Because of its compelling anti-inflammatory effects, PTX may be an ideal candidate for use as an immunomodulatory adjunct to resuscitation fluid.

Attenuation of tumor necrosis factor-induced endothelial cell cytotoxicity and neutrophil chemiluminescence

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng, H.; Crowley, J.J.; Chan, J.C.

Our laboratory has previously shown that the administration of tumor necrosis factor (TNF), a cytokine produced by activated mononuclear cells, to guinea pigs produces a syndrome similar to gram-negative sepsis or ARDS. Pentoxifylline (PTX), a methylxanthine, protects against TNF-induced and sepsis-induced acute lung injury in vivo. We now report on in vitro cellular studies of PMN-mediated cellular injury and its attenuation. We studied TNF-induced bovine pulmonary artery endothelial cell (EC) cytotoxicity both with and without PMN. A 51Cr release assay was used to measure EC damage. Further, we investigated PMN function in response to TNF by measuring chemiluminescence. Agents thatmore » attenuate EC damage and PMN activation were evaluated in the above assays. Results revealed that TNF causes EC injury (p less than 0.05) and PMN increase TNF-induced EC injury. Furthermore, PTX, aminophylline (AMPH), caffeine, and forskolin attenuate TNF-induced EC cytotoxicity only in the presence of PMN (p less than 0.05). Of interest, dibutyryl cAMP (DBcAMP) protects EC from TNF-induced injury both with and without PMN. Agents that may increase cAMP levels in PMN (PTX, DBcAMP, forskolin, isobutyl methylxanthine, and terbutaline) significantly attenuate TNF-induced PMN chemiluminescence (p less than 0.05). We conclude that TNF causes EC damage and PMN increase this damage. Furthermore, PTX, AMPH, caffeine, and forskolin can attenuate TNF-induced EC injury in the presence of PMN, whereas DBcAMP attenuates TNF-induced EC injury with and without PMN. In addition, agents that may increase intracellular cAMP levels in PMN can attenuate TNF-induced PMN chemiluminescence. Thus, these agents likely attenuate TNF-induced PMN-mediated EC injury through their inhibitory effects on PMN.« less

[Clinical studies in peripheral arterial occlusive disease: update from the aspects of a meta-narrative review].

PubMed

Melzer, Jörg; Saller, Reinhard

2013-01-01

Atherosclerosis is a systemic disease. Its association with the metabolic syndrome requires a multimodal therapy setting, to alleviate symptoms and for primary and secondary prevention. In the planning of the therapy, information about evidence of the interventions and a rationale for reasonable combinations are important. For compiling a meta-narrative review (MNR) on the evidence of complementary and conventional pharmaco-therapy in peripheral arterial occlusive disease (PAOD), the literature was searched for meta-analyses of randomized controlled trials (RCTs). These were evaluated taking into account network-pharmacological aspects and research parameters. 4 suitable meta-analyses were found. In comparison to placebo, treatments with verum showed a significant improvement of the maximum walking distance of 63.5 m (95% confidence interval (CI) 27.11-99.91 m; Padma 28, Tibetan Formula), 41.3 m (95% CI -7.1-89.7 m; cilostazol, phosphodiesterase IIl inhibitor), 43.8 m (95% CI 14.1-73.6 m; pentoxifylline, rheological drug), and 71.2 m (95% CI 13.3-129.0 m; naftidrofuryl, rheological drug). Only for Padma 28, clinical relevance, defined as an increase of the maximum walking distance by >100 m, was analyzed and reached by 18.2% of the verum and 2.1% of the placebo patients (odds ratio 10; 95% CI 3.03-33.33). 1 conventional and 1 complementary drug additionally showed to have significant pleiotropic effects (Padma 28 and cilostazol (e.g. reduction of triglycerides)). According to meta-analytic evidence, naftidrofuryl and Padma 28 show clinically relevant efficacy for the treatment of early stages of PAOD. The extent to which the theoretically possible combination of different drugs contributes to improve the systemic disease under a network-pharmacological rationale remains to be shown in a multi-armed RCT.

Trypanosoma cruzi-induced depressive-like behavior is independent of meningoencephalitis but responsive to parasiticide and TNF-targeted therapeutic interventions.

PubMed

Vilar-Pereira, Glaucia; Silva, Andrea Alice da; Pereira, Isabela Resende; Silva, Rafael Rodrigues; Moreira, Otacílio Cruz; de Almeida, Luciana Rodrigues; de Souza, Amanda Santos; Rocha, Monica Santos; Lannes-Vieira, Joseli

2012-10-01

Inflammatory cytokines and microbe-borne immunostimulators have emerged as triggers of depressive behavior. Behavioral alterations affect patients chronically infected by the parasite Trypanosoma cruzi. We have previously shown that C3H/He mice present acute phase-restricted meningoencephalitis with persistent central nervous system (CNS) parasitism, whereas C57BL/6 mice are resistant to T. cruzi-induced CNS inflammation. In the present study, we investigated whether depression is a long-term consequence of acute CNS inflammation and a contribution of the parasite strain that infects the host. C3H/He and C57BL/6 mice were infected with the Colombian (type I) and Y (type II) T. cruzi strains. Forced-swim and tail-suspension tests were used to assess depressive-like behavior. Independent of the mouse lineage, the Colombian-infected mice showed significant increases in immobility times during the acute and chronic phases of infection. Therefore, T. cruzi-induced depression is independent of active or prior CNS inflammation. Furthermore, chronic depressive-like behavior was triggered only by the type I Colombian T. cruzi strain. Acute and chronic T. cruzi infection increased indoleamine 2,3-dioxygenase (IDO) expression in the CNS. Treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine abrogated the T. cruzi-induced depressive-like behavior. Moreover, treatment with the parasiticide drug benznidazole abrogated depression. Chronic T. cruzi infection of C57BL/6 mice increased tumor necrosis factor (TNF) expression systemically but not in the CNS. Importantly, TNF modulators (anti-TNF and pentoxifylline) reduced immobility. Therefore, direct or indirect parasite-induced immune dysregulation may contribute to chronic depressive disorder in T. cruzi infection, which opens a new therapeutic pathway to be explored. Copyright © 2012 Elsevier Inc. All rights reserved.

Viability of randomized skin flaps-an experimental study in rats.

PubMed

António, Nsingi N; Monte Alto Costa, Andréa; Marques, Ruy G

2017-01-01

Randomized skin flaps are extensively used in plastic surgery, but the possibility of necrosis has challenged their use. Several studies have been conducted aiming to find ways to reduce the occurrence of necrosis. We evaluated the effects of pentoxifylline (PTX) and hyaluronidase (HLD), each alone or combined, on randomized rat skin flaps. Fifty male Wistar rats were divided into five groups of 10 animals each: control I, control II, PTX, HLD, PTX-HLD. Substances were administered from the first to the 14th postoperative day. The necrotic area was measured on the seventh and 14th postoperative day; the animals were killed on the 14th day, when samples were collected for histologic and immunohistochemical examination. On the seventh day, percentage of the necrotic area was significantly reduced in PTX, HLD, and PTX-HLD animals compared with control groups. On 14th day, percentage of the necrotic area in PTX, HDL, and PTX-HLD groups was also significantly reduced compared with control groups. PTX and PTX-HLD showed a significant reduction in dermis cellularity, V V of macrophages, and myofibroblasts compared with control groups; PTX showed a significant enhancement of L V of blood vessels compared with all other groups. The use of each substance alone or combined increased flap viability compared with control groups. On the seventh day, PTX exhibited lower viability than HLD, whereas on the 14th day there was no difference between treated groups. PTX alone enhanced the L V of blood vessels, whereas PTX-HLD did not. However, PTX-HLD was more effective in decreasing the dermis cellularity and macrophage V V than HLD alone. Copyright © 2016 Elsevier Inc. All rights reserved.

Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity

PubMed Central

Massart, Julie; Begriche, Karima; Moreau, Caroline; Fromenty, Bernard

2017-01-01

Background Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. Aim The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a data-mining analysis using different queries including drug-induced liver injury (or DILI), drug-induced hepatotoxicity, fatty liver, nonalcoholic fatty liver disease (or NAFLD), steatosis and obesity. The main data from the collected articles are reported in this review and when available, some pathophysiological hypotheses are put forward. Relevance for patients Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen, halothane, methotrexate, rosiglitazone, stavudine and tamoxifen. For some of these drugs, experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Other drugs such as pentoxifylline, phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not. Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes, hyperlipidemia and coronary heart disease, it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening. PMID:28691103

Seasonality effects on pharmaceuticals and s-triazine herbicides in wastewater effluent and surface water from the Canadian side of the upper Detroit River.

PubMed

Hua, Wen Yi; Bennett, Erin R; Maio, Xui-Sheng; Metcalfe, Chris D; Letcher, Robert J

2006-09-01

The influence of seasonal changes in water conditions and parameters on several major pharmacologically active compounds (PhACs) and s-triazine herbicides was assessed in the wastewater and sewage treatment plant (WSTP) effluent as well as the downstream surface water from sites on the Canadian side of the upper Detroit River, between the Little River WSTP and near the water intake of a major drinking water treatment facility for the City of Windsor (ON, Canada). The assessed PhACs were of neutral (carbamazepine, cotinine, caffeine, cyclophosphamide, fluoxetine, norfluoxetine, pentoxifylline, and trimethoprim) and acidic (ibuprofen, bezafibrate, clofibric acid, diclofenac, fenoprofen, gemfibrozil, indomethacin, naproxen, and ketoprofen) varieties. The major assessed s-triazine herbicides were atrazine, simazine, propazine, prometon, ametryn, prometryn, and terbutryn. At sampling times from September 2002 to June 2003, 15 PhACs were detected in the WSTP effluent at concentrations ranging from 1.7 to 1244 ng/L. The PhAC concentrations decreased by as much 92 to 100% at the Little River/Detroit River confluence because of the river dilution effect, with further continual decreases at sites downstream from the WSTP. The only quantifiable s-triazine in WSTP effluent, atrazine, ranged from 6.7 to 200 ng/L and was higher in Detroit River surface waters than in WSTP effluent. Only carbamazepine, cotinine, and atrazine were detectable at the low-nanogram and subnanogram levels in surface waters near a drinking water intake site. Unlike the PhACs, atrazine in the Detroit River is not attributable to point sources, and it is heavily influenced by seasonal agricultural usage and runoff. Detroit River surface water concentrations of carbamazepine, cotinine, and atrazine may present a health concern to aquatic wildlife and to humans via the consumption of drinking water.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cazanave, Sophie; Vadrot, Nathalie; Tinel, Marina

Fas stimulation recruits neutrophils and activates macrophages that secrete tumor necrosis factor-{alpha} (TNF-{alpha}), which aggravates Fas-mediated liver injury. To determine whether nonsteroidal anti-inflammatory drugs modify these processes, we challenged 24-hour-fasted mice with the agonistic Jo2 anti-Fas antibody (4 {mu}g/mouse), and treated the animals 1 h later with saline or ibuprofen (250 mg/kg), a dual cyclooxygenase (COX)-1 and COX-2 inhibitor. Ibuprofen attenuated the Jo2-mediated recruitment/activation of myeloperoxidase-secreting neutrophils/macrophages in the liver, and attenuated the surge in serum TNF-{alpha}. Ibuprofen also minimized hepatic glutathione depletion, Bid truncation, caspase activation, outer mitochondrial membrane rupture, hepatocyte apoptosis and the increase in serum alanine aminotransferasemore » (ALT) activity 5 h after Jo2 administration, to finally decrease mouse mortality at later times. The concomitant administration of pentoxifylline (decreasing TNF-{alpha} secretion) and infliximab (trapping TNF-{alpha}) likewise attenuated the Jo2-mediated increase in TNF-{alpha}, the decrease in hepatic glutathione, and the increase in serum ALT activity 5 h after Jo2 administration. The concomitant administration of the COX-1 inhibitor, SC-560 (10 mg/kg) and the COX-2 inhibitor, celecoxib (40 mg/kg) 1 h after Jo2 administration, also decreased liver injury 5 h after Jo2 administration. In contrast, SC-560 (10 mg/kg) or celecoxib (40 or 160 mg/kg) given alone had no significant protective effects. In conclusion, secondary TNF-{alpha} secretion plays an important role in Jo2-mediated glutathione depletion and liver injury. The combined inhibition of COX-1 and COX-2 by ibuprofen attenuates TNF-{alpha} secretion, glutathione depletion, mitochondrial alterations, hepatic apoptosis and mortality in Jo2-treated fasted mice.« less

Preventing necrotizing enterocolitis by food additives in neonates: A network meta-analysis revealing the efficacy and safety.

PubMed

Yu, Wentao; Sui, Wu; Mu, Linsong; Yi, Wenying; Li, Haijuan; Wei, Liqin; Yin, Weihong

2017-05-01

Necrotizing enterocolitis (NEC) is a serious multifactorial gastrointestinal disease which is often discovered in premature infants. Various additives have been used to prevent NEC; yet, their relative efficacy and safety remain disputed. This study aims to compare the efficacy and safety of 5 food additives, namely, probiotics, probiotics + fructo-oligosaccharides, pentoxifylline, arginine, and lactoferrin in preventing NEC in neonates. Embase, PubMed, and Cochrane Library had been searched for all eligible randomized control trials. Odds ratios (ORs) were estimated for dichotomous data and mean differences with 95% credible intervals (CrIs) were estimated for continuous data. Surface under the cumulative ranking curve was used to rank efficacy and safety of the prevention methods on each endpoint. A total of 27 eligible studies with 4649 preterm infants were included in this network meta-analysis (NMA), and the efficacy and safety of 5 food additives were evaluated. Probiotic and arginine exhibited better preventive efficacy compared with placebo (OR = 0.50, 95% CrIs: 0.32-0.73; OR = 0.30, 95% CrIs: 0.12-0.73, respectively). Only probiotic achieved a considerable decrease in the risk of mortality compared to placebo (OR = 0.68, 95% CrIs: 0.46-0.98). NEC patients with lactoferrin appeared to have lower incidence of sepsis than those of placebo (OR = 0.13, 95% CrIs: 0.03-0.61) or probiotic (OR = 0.18, 95% CrIs: 0.03-0.83). Based on this NMA, probiotics had the potential to be the most preferable additive, since it exhibited a significant superiority for NEC and mortality as well as a relatively balanced performance in safety.

[Influences of high-voltage electrical burns on microcirculation perfusion on serosal surface of small intestine of rats and the interventional effects of pentoxifylline].

PubMed

Zhang, Q F; Xu, S J; Liang, L M; Feng, J K; Xu, Y F; Tu, L L

2017-03-20

Objective: To investigate influences of high-voltage electrical burns on microcirculation perfusion on serosal surface of small intestine of rats and the interventional effects of pentoxifylline (PTX). Methods: Totally 180 SD rats were divided into sham injury group, simple electrical burn group, and treatment group according to the random number table, with 60 rats in each group. The electrical current was applied to the outside proximal part of left forelimb of rats and exited from the outside proximal part of right hind limb of rats. Rats in simple electrical burn group and treatment group were inflicted with high-voltage electrical burn wounds of 1cm×1cm at current entrances and exits, with the voltage regulator and experimental transformer. Rats in sham injury group were sham injured through connecting the same equipments without electricity. At 2 min post injury, rats in sham injury group and simple electrical burn group were intraperitoneally injected with 2 mL normal saline, and rats in treatment group were injected with 2 mL PTX injection (50 mg/mL). At 15 min before injury and 5 min, 1 h, 2 h, 4 h, and 8 h post injury, 10 rats in each group were selected to collect blood of heart respectively. Serum were separated from the blood to determine the level of soluble vascular cell adhesion molecule-1(sVCAM-1) with enzyme-linked immunosorbent assay method. The number of adhesional leukocyte in mesenteric venule of rats was determined with Bradford variable projection microscope system. The microcirculation perfusion on serosal surface of small intestine of rats was detected with laser Doppler perfusion imager. Data were processed with analysis of variance of factorial design and LSD test. Results: (1) At 5 min, 1 h, 2 h, 4 h, 8 h post injury, the serum content of sVCAM-1 in rats of simple electrical burn group were (8 502±1 158), (11 793±3 310), (9 960±2 146), (9 708±1 429), (7 292±1 386) ng/mL respectively, higher than that in sham injury group and treatment group [ (1 897±946), (1 882±940), (1 882±938), (1 888±946), (1 884±942) ng/mL, and (6 840±1 558), (6 742±2 465), (5 625±2 593), (2 373±1 463), (5 187±2 797) ng/mL, respectively, with P values below 0.001]. The serum content of sVCAM-1 in rats of sham injury group and treatment group at all time points post injury, except 4 h post injury of treatment group, was higher than that of the same group at 15 min before injury (with P values below 0.001). (2) At all time points post injury, the number of adhesional leukocyte in mesenteric venule of rats in simple electrical burn group was higher than that in sham injury group and treatment group (with P values below 0.001). The number of adhesional leukocyte in mesenteric venule of rats in simple electrical burn group and treatment group at all time points post injury was higher than that of the same group at 15 min before injury (with P values below 0.001). (3) At all time points post injury, the microcirculation perfusion on serosal surface of small intestine of rats in simple electrical burn group was lower than that in sham injury group and treatment group (with P values below 0.001). The microcirculation perfusion on serosal surface of small intestine of rats in simple electrical burn group and treatment group at all time points post injury was lower than that of the same group at 15 min before injury (with P values below 0.001). Conclusions: High-voltage electrical burns can increase the serum content of sVCAM-1, the number of adhesional leukocyte in mesenteric venule, and reduce microcirculation perfusion on serosal surface of small intestine of rats. PTX can inhibit secretion of serum sVCAM-1, reduce the number of adhensional leukocyte in mesenteric venule to alleviate microcirculation disturbance caused by high-voltage electrical burns.

Case Report: Industrial X-Ray Injury Treated With Non-Cultured Autologous Adipose-Derived Stromal Vascular Fraction (SVF).

PubMed

Iddins, C J; Cohen, S R; Goans, R E; Wanat, R; Jenkins, M; Christensen, D M; Dainiak, N

2016-08-01

Local cutaneous injuries induced by ionizing radiation (IR) are difficult to treat. Many have reported local injection of adipose-derived stromal vascular fraction (SVF), often with additional therapies, as an effective treatment of IR-induced injury even after other local therapies have failed. The authors report a case of a locally recurrent, IR-induced wound that was treated with autologous, non-cultured SVF without other concurrent therapy. A nondestructive testing technician was exposed to 130 kVp x rays to his non-dominant right thumb on 5 October 2011. The wound healed 4 mo after initial conservative therapy with oral/topical α-tocopherol, oral pentoxifylline, naproxen sodium, low-dose oral steroids, topical steroids, hyperbaric oxygen therapy (HBOT), oral antihistamines, and topical aloe vera. Remission lasted approximately 17 mo with one minor relapse in July 2012 after minimal trauma and subsequent healing. Aggressive wound breakdown during June 2013 required additional therapy with HBOT. An erythematous, annular papule developed over the following 12 mo (during which time the patient was not undergoing prescribed treatment). Electron paramagnetic resonance (EPR) done more than 2 mo after exposure to IR revealed dose estimates of 14 ± 3 Gy and 19 ± 6 Gy from two centers using different EPR techniques. The patient underwent debridement of the 0.5 cm papular area, followed by SVF injection into and around the wound bed and throughout the thumb without complication. Eleven months post SVF injection, the patient has been essentially asymptomatic with an intact integument. These results raise the possibility of prolonged benefit from SVF therapy without the use of cytokines. Since there is currently no consensus on the use of isolated SVF therapy in chronic, local IR-induced injury, assessment of this approach in an appropriately powered, controlled trial in experimental animals with local radiation injury appears to be indicated.

A peek into the drug development scenario of endometriosis - A systematic review.

PubMed

Goenka, Luxitaa; George, Melvin; Sen, Maitrayee

2017-06-01

Endometriosis is a gynaecological disease that is characterised by the presence of endometrium like tissue-epithelium and stroma that develops outside the uterine cavity, which is responsible for pelvic pain and infertility. Even though several medical therapies exist for the treatment of endometriosis, each of the drug class has its own limitations such as cost of treatment, side-effects and its short-term effect on the symptoms of endometriosis. In this review, we have attempted to summarize the current status and challenges of drug development for endometriosis. A systematic review was done and all the RCTs were selected from the identified hits. We included studies that explored the usage of therapeutic drugs on endometriosis patients from inception till November 2016. The search term used was 'Endometriosis' using PubMed and Clinicaltrials.gov. For the final analysis, 60 articles were analyzed and we identified the newly emerging drug therapies for endometriosis treatment and have briefed their current status and challenges in drug development for endometriosis. The quality of the selected studies was assessed based on the degree of bias. The current classes of drugs that have shown promising therapeutic results include Gonadotropin- releasing hormone (GnRH) antagonists, aromatase inhibitors (AI), and selective progesterone and estrogen receptor modulators, dopamine receptor-2-agonists and statins. The drugs that failed midway during development include tanezumab, rosiglitazone, infliximab, pentoxifylline, telapristone acetate, asoprisnil and raloxifene. From the literature review, it appears that the most promising molecules for the treatment of endometriosis in the near future include elagolix, mifepristone, TAK-385, KLH-2109 and ASP1707 and cabergoline. It remains to be seen if these molecules would succeed large phase 3 clinical trials and overcome the regulatory hurdles to become an essential tool in the gynaecologist's armamentarium against endometriosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Artificial oocyte activation in intracytoplasmic sperm injection cycles using testicular sperm in human in vitro fertilization.

PubMed

Kang, Hee Jung; Lee, Sun-Hee; Park, Yong-Seog; Lim, Chun Kyu; Ko, Duck Sung; Yang, Kwang Moon; Park, Dong-Wook

2015-06-01

Artificial oocyte activation (AOA) is an effective method to avoid total fertilization failure in human in vitro fertilization-embryo transfer (IVF-ET) cycles. AOA performed using a calcium ionophore can induce calcium oscillation in oocytes and initiate the fertilization process. We evaluated the usefulness of AOA with a calcium ionophore in cases of total fertilization failure in previous cycles and in cases of severe male factor infertility patients with non-motile spermatozoa after pentoxifylline (PF) treatment. The present study describes 29 intracytoplasmic sperm injection (ICSI)-AOA cycles involving male factor infertility at Cheil General Hospital from January 2006 to June 2013. Patients were divided into two groups (control, n=480; AOA, n=29) depending on whether or not AOA using a calcium ionophore (A23187) was performed after testicular sperm extraction-ICSI (TESE-ICSI). The AOA group was further split into subgroups according to sperm motility after PF treatment: i.e., motile sperm-injected (n=12) and non-motile sperm-injected (n=17) groups (total n=29 cycles). The good embryo rate (52.3% vs. 66.9%), pregnancy rate (20.7% vs. 52.1%), and delivery rate (10.3% vs. 40.8%) were lower in the PF/AOA group than in the control group. When evaluating the effects of restoration of sperm motility after PF treatment on clinical outcomes there was no difference in fertilization rate (66.6% vs. 64.7% in non-motile and motile sperm, respectively), pregnancy rate (17.6% vs. 33.3%), or delivery rate (5.9% vs. 16.7%) between the two groups. We suggest that oocyte activation is a useful method to ensure fertilization in TESE-ICSI cycles regardless of restoration of sperm motility after PF treatment. AOA may be useful in selected patients who have a low fertilization rate or total fertilization failure.

Inflammatory mechanisms and oxidative stress in Peyronie's disease: therapeutic "rationale" and related emerging treatment strategies.

PubMed

Paulis, Gianni; Brancato, Tommaso

2012-02-01

Peyronie's disease (PD) is a connective tissue disorder characterized by a fibrous plaque involving the tunica albuginea of the penis. The inelastic fibrous plaque leads to a penile curvature. Several Authors have suggested an immunological genesis of this disease, others have linked PD with Dupuytren's contracture. Signs of this disease are curvature, penile pain, penile deformity, difficulty with coitus, shortening, hinging, narrowing and erectile dysfunction. The natural history of PD and the clinical course can develop from spontaneous resolution of symptoms to progressive penile deformity and impotence. Surgical treatment is indicated when patients fail the conservative medical treatment and however, only in case of disease stabilization with a condition of impossibility of penetration. The medical treatment is indicated in the development stage of PD for at least one year after diagnosis and whenever in case of penile pain. Current non-surgical therapy includes vitamin-E, verapamil, para-aminobenzoate, propoleum, colchicine, carnitine, tamoxifen, interferons, collagenase, hyaluronidase, cortisone, pentoxifylline, superoxide dismutase, iontophoresis, radiation, extracorporeal shock wave therapy (ESWT) and the penile extender. The etiology of this fibrotic disease is not widely known, although in recent years pathophysiological knowledge has evolved and new studies propose the penile trauma as cause of the disease. The penile trauma results in a delamination of the tunica albuginea with a consequent small hematoma, then the process evolves as an inflammation with accumulation of inflammatory cells and production of reactive oxygen species (ROS). In the course of the inflammation, Peyronie's disease occurs due to the activation of nuclear factor kappa-B, that induces the production of inducible nitric oxide synthase (iNOS), with an increase of nitric oxide, leading to increased production of peroxynitrite anion. All these processes result in the proliferation of fibroblasts and myo-fibroblasts and excessive production of collagen between the layers of the tunica albuginea (penile plaque). Referring to the current knowledge of inflammatory and oxidative mechanisms of PD, a possible therapeutic strategy is then analyzed. © 2012 Bentham Science Publishers

Rationale of combination therapy with antioxidants in medical management of Peyronie’s disease: results of clinical application

PubMed Central

Paulis, Gianni; Paulis, Andrea; Romano, Gennaro; Barletta, Davide; Fabiani, Andrea

2017-01-01

Peyronie’s disease (PD) is a connective tissue disorder involving the tunica albuginea of the corpora cavernosa of the penis. We have published several studies describing a “combined therapy” for PD patients, but the present study aims to clearly demonstrate how the association between various antioxidants in PD treatment can significantly increase the likelihood of therapeutic success. We used the following substances: silymarin, ginkgo biloba, vitamin E, bilberry, topical diclofenac sodium, and pentoxifylline (PTX). We analyzed the therapeutic impact and possible side effects of one or more antioxidants in patients with early-stage PD. To clearly prove that it is possible to achieve better results when combining more than one agent, we designed this study with five treatment groups, corresponding, respectively, to the administration of a single oral antioxidant; two oral antioxidants; three oral antioxidants; five oral antioxidants + local diclofenac; and five oral antioxidants + local diclofenac + PTX by perilesional injection. One hundred and twenty patients were assigned to five groups of treatment designed according to the abovementioned study aim. Outcomes after 6 months of treatment showed that combined antioxidant therapy is effective in treating PD. Statistical analysis showed significant differences between the treatment groups with regard to: improvement and disappearance of penile pain; percentage of reduction in the volume of penile plaque; reduction in penile curvature; recovery of erectile function in patients with erectile dysfunction; increase in the International Index of Erectile Function score; and reduction of psychosexual impact. Furthermore, we observed that the clinical efficacy of combined therapy is greater when topical use of diclofenac gel and perilesional injection of PTX are added to oral treatment with more than one antioxidant. Although several articles have already been published reporting the effectiveness of combined treatment in PD, this is the first study clearly proving how, as the number of substances used in treatment rises, a proportionally greater therapeutic effect is achieved. PMID:28791261

Influenza ("Bird Flu"), inflammation and anti-inflammatory/analgesic drugs.

PubMed

Rainsford, K D

2006-03-01

The spectre of an influenza pandemic is being widely mooted. Most of the strategies explored to date for controlling or treating the condition have centred on controlling the spread of the infection, the use of vaccines or anti-viral agents. There has been relatively little discussion about treating the lung and systemic inflammatory reactions that occur during influenza infection. In this review a range of therapeutic agents are proposed to treat the inflammatory reactions, principally in the lung as well as the systemic cytokine-mediated immuno-inflammatory reactions that may be a major cause of the morbidity and mortality associated with influenza infections. Among these are pentoxifylline, the statins, the macrolide antibiotics (e.g. azithromycin, clarithromycin, erythromycin), resveratrol (a component of wine and fruits with inhibitory effects on influenza virus replication) and nutraceuticals (including those that contain flavonoids, the marine oils eicosapentanoic and docosanoic acids or the green-lipped mussel extract, Liprinol which may by virtue of the inhibitory effects on the production or actions of pro-inflammatory cytokines, be useful for their anti-inflammatory actions. The efficacy, mode of actions and side effects of non-steroidal anti-inflammatory drugs (NSAIDs) are considered. There are a number of issues relating to their use in treating the inflammatory reactions in the respiratory tract. Among these are the development of gastro-intestinal ulcers and bleeding and hepato-renal reactions in patients that may because of severe systemic inflammation be prone to the development of these adverse reactions. There are also theoretical issues concerning the impact of COX-1 mediating reduction in prostaglandin and increased cytokine production that might have some negative consequences for respiratory inflammation.In conclusion, further consideration should be given to exploring the actions of these anti-inflammatory agents to control the respiratory inflammatory in influenza infections which can have serious consequences for the outcome of the infection.

Artificial oocyte activation in intracytoplasmic sperm injection cycles using testicular sperm in human in vitro fertilization

PubMed Central

Kang, Hee Jung; Lee, Sun-Hee; Park, Yong-Seog; Lim, Chun Kyu; Ko, Duck Sung; Yang, Kwang Moon

2015-01-01

Objective Artificial oocyte activation (AOA) is an effective method to avoid total fertilization failure in human in vitro fertilization-embryo transfer (IVF-ET) cycles. AOA performed using a calcium ionophore can induce calcium oscillation in oocytes and initiate the fertilization process. We evaluated the usefulness of AOA with a calcium ionophore in cases of total fertilization failure in previous cycles and in cases of severe male factor infertility patients with non-motile spermatozoa after pentoxifylline (PF) treatment. Methods The present study describes 29 intracytoplasmic sperm injection (ICSI)-AOA cycles involving male factor infertility at Cheil General Hospital from January 2006 to June 2013. Patients were divided into two groups (control, n=480; AOA, n=29) depending on whether or not AOA using a calcium ionophore (A23187) was performed after testicular sperm extraction-ICSI (TESE-ICSI). The AOA group was further split into subgroups according to sperm motility after PF treatment: i.e., motile sperm-injected (n=12) and non-motile sperm-injected (n=17) groups (total n=29 cycles). Results The good embryo rate (52.3% vs. 66.9%), pregnancy rate (20.7% vs. 52.1%), and delivery rate (10.3% vs. 40.8%) were lower in the PF/AOA group than in the control group. When evaluating the effects of restoration of sperm motility after PF treatment on clinical outcomes there was no difference in fertilization rate (66.6% vs. 64.7% in non-motile and motile sperm, respectively), pregnancy rate (17.6% vs. 33.3%), or delivery rate (5.9% vs. 16.7%) between the two groups. Conclusion We suggest that oocyte activation is a useful method to ensure fertilization in TESE-ICSI cycles regardless of restoration of sperm motility after PF treatment. AOA may be useful in selected patients who have a low fertilization rate or total fertilization failure. PMID:26161332

Antifungal activity of HWA-138 and amphotericin B in experimental systemic candidiasis.

PubMed Central

Wasan, K M; Vadiei, K; Luke, D R; Keyhani, A; White, R A; McQueen, T J; Mehta, R; Lopez-Berestein, G

1991-01-01

HWA-138, a pentoxifylline analog, has been shown to increase yeast urinary clearance and to reduce yeast counts in the kidneys of rats infected with Candida albicans. Furthermore, HWA-138 has also been shown to prevent amphotericin B-induced acute renal failure in rats. We report here on the effects of HWA-138 alone and in combination with amphotericin B in the treatment of systemic candidiasis in mice. When single doses of HWA-138 were administered intravenously (10, 25, or 50 mg/kg of body weight) into infected mice, no significant improvement in survival was observed. In infected mice treated intravenously with multiple doses of HWA-138 (10, 25, or 50 mg/kg once daily for 5 consecutive days), a significant increase in survival time was seen only in animals also receiving 25 mg of HWA-138 per kg (14 +/- 3 days test versus 9 +/- 1 days control; P less than 0.05). The coadministration of subtherapeutic doses of amphotericin B and HWA-138 resulted in increased survival time. Combination therapy with amphotericin B (0.1-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) resulted in a significant increase in survival time over controls (19 +/- 4, 19 +/- 5, and 21 +/- 9 days, respectively, versus 9 +/- 3 days; P less than 0.05). Combination therapy with amphotericin B (0.2-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) also resulted in a significant increase in survival time over controls (24 +/- 6, 24 +/- 6, and 24 +/- 6, respectively, versus 9 +/- 3 days; P less than 0.05). Combination therapy with amphotericin B (0.2-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) also resulted in a significant increase in survival time over controls (24 +/- 6, 24 +/- 6, and 24 +/- 6, respectively, versus 9 +/- 3 days; P < 0.05). Variance analysis of these findings indicate synergistic activity between amphotericin B and HWA-138 in the treatment of experimental candidiasis in mice. PMID:1759826

Pentoxifylline and the proteasome inhibitor MG132 induce apoptosis in human leukemia U937 cells through a decrease in the expression of Bcl-2 and Bcl-XL and phosphorylation of p65.

PubMed

Bravo-Cuellar, Alejandro; Hernández-Flores, Georgina; Lerma-Díaz, José Manuel; Domínguez-Rodríguez, Jorge Ramiro; Jave-Suárez, Luis F; De Célis-Carrillo, Ruth; Aguilar-Lemarroy, Adriana; Gómez-Lomeli, Paulina; Ortiz-Lazareno, Pablo Cesar

2013-02-28

In Oncology, the resistance of the cancerous cells to chemotherapy continues to be the principal limitation. The nuclear factor-kappa B (NF-κB) transcription factor plays an important role in tumor escape and resistance to chemotherapy and this factor regulates several pathways that promote tumor survival including some antiapoptotic proteins such as Bcl-2 and Bcl-XL. In this study, we investigated, in U937 human leukemia cells, the effects of PTX and the MG132 proteasome inhibitor, drugs that can disrupt the NF-κB pathway. For this, we evaluated viability, apoptosis, cell cycle, caspases-3, -8, -9, cytochrome c release, mitochondrial membrane potential loss, p65 phosphorylation, and the modification in the expression of pro- and antiapoptotic genes, and the Bcl-2 and Bcl-XL antiapoptotic proteins. The two drugs affect the viability of the leukemia cells in a time-dependent manner. The greatest percentage of apoptosis was obtained with a combination of the drugs; likewise, PTX and MG132 induce G1 phase cell cycle arrest and cleavage of caspases -3,-8, -9 and cytochrome c release and mitochondrial membrane potential loss in U937 human leukemia cells. In these cells, PTX and the MG132 proteasome inhibitor decrease p65 (NF-κB subunit) phosphorylation and the antiapoptotic proteins Bcl-2 and Bcl-XL. We also observed, with a combination of these drugs overexpression of a group of the proapoptotic genes BAX, DIABLO, and FAS while the genes BCL-XL, MCL-1, survivin, IκB, and P65 were downregulated. The two drugs used induce apoptosis per se, this cytotoxicity was greater with combination of both drugs. These observations are related with the caspases -9, -3 cleavage and G1 phase cell cycle arrest, and a decrease in p65 phosphorylation and Bcl-2 and Bcl-XL proteins. As well as this combination of drugs promotes the upregulation of the proapoptotic genes and downregulation of antiapoptotic genes. These observations strongly confirm antileukemic potential.

Venous leg ulcers

PubMed Central

2008-01-01

Introduction Leg ulcers usually occur secondary to venous reflux or obstruction, but 20% of people with leg ulcers have arterial disease, with or without venous disorders. Between 1.5 and 3.0/1000 people have active leg ulcers. Prevalence increases with age to about 20/1000 in people aged over 80 years. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of standard treatments, adjuvant treatments, and organisational interventions for venous leg ulcers? What are the effects of interventions to prevent recurrence of venous leg ulcers? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 80 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: compression bandages and stockings, cultured allogenic (single or bilayer) skin replacement, debriding agents, dressings (cellulose, collagen, film, foam, hyaluronic acid-derived, semi-occlusive alginate), hydrocolloid (occlusive) dressings in the presence of compression, intermittent pneumatic compression, intravenous prostaglandin E1, larval therapy, laser treatment (low-level), leg ulcer clinics, multilayer elastic system, multilayer elastomeric (or non-elastomeric) high-compression regimens or bandages, oral treatments (aspirin, flavonoids, pentoxifylline, rutosides, stanozolol, sulodexide, thromboxane alpha2 antagonists, zinc), peri-ulcer injection of granulocyte-macrophage colony-stimulating factor, short-stretch bandages, single-layer non-elastic system, skin grafting, superficial vein surgery, systemic mesoglycan, therapeutic ultrasound, self-help (advice to elevate leg, advice to keep leg active, advice to modify diet, advice to stop smoking, advice to reduce weight), and topical treatments (antimicrobial agents, autologous platelet lysate, calcitonin gene-related peptide plus vasoactive intestinal polypeptide, freeze-dried keratinocyte lysate, mesoglycan, negative-pressure recombinant keratinocyte growth factor, platelet-derived growth factor). PMID:19445798

Venous leg ulcers

PubMed Central

2011-01-01

Introduction Leg ulcers usually occur secondary to venous reflux or obstruction, but 20% of people with leg ulcers have arterial disease, with or without venous disorders. Between 1.5 and 3.0/1000 people have active leg ulcers. Prevalence increases with age to about 20/1000 in people aged over 80 years. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of standard treatments, adjuvant treatments, and organisational interventions for venous leg ulcers? What are the effects of advice about self-help interventions in people receiving usual care for venous leg ulcers? What are the effects of interventions to prevent recurrence of venous leg ulcers? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 101 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: compression bandages and stockings, cultured allogenic (single or bilayer) skin replacement, debriding agents, dressings (cellulose, collagen, film, foam, hyaluronic acid-derived, semi-occlusive alginate), hydrocolloid (occlusive) dressings in the presence of compression, intermittent pneumatic compression, intravenous prostaglandin E1, larval therapy, laser treatment (low-level), leg ulcer clinics, multilayer elastic system, multilayer elastomeric (or non-elastomeric) high-compression regimens or bandages, oral treatments (aspirin, flavonoids, pentoxifylline, rutosides, stanozolol, sulodexide, thromboxane alpha2 antagonists, zinc), peri-ulcer injection of granulocyte-macrophage colony-stimulating factor, self-help (advice to elevate leg, to keep leg active, to modify diet, to stop smoking, to reduce weight), short-stretch bandages, single-layer non-elastic system, skin grafting, superficial vein surgery, systemic mesoglycan, therapeutic ultrasound, and topical treatments (antimicrobial agents, autologous platelet lysate, calcitonin gene-related peptide plus vasoactive intestinal polypeptide, freeze-dried keratinocyte lysate, mesoglycan, negative pressure, recombinant keratinocyte growth factor, platelet-derived growth factor). PMID:22189344

Salivary levels of TNF-α in patients with recurrent aphthous stomatitis: A cross-sectional study.

PubMed

Chaudhuri, Kanad; Nair, Keerthi Krishnankutty; Ashok, Lingappa

2018-01-01

Background. Recurrent aphthous stomatitis (RAS) is a disorder characterized by recurring ulcers involving the oral mucosa in patients with no other signs of disease. The current concept of etiopathogenesis is that RAS is a clinical syndrome with several possible etiologies. The process seen in RAS is probably initiated through an as yet unidentified antigenic stimulation of the mucosal keratinocytes, which stimulates secretion of T-cell activation cytokines ‒ interleukins and tumor necrosis factor alpha (TNF-α). TNF-α causes inflammation by its effect on endothelial cell adhesion and neutrophil chemotaxis. The rele-vance of TNF-α to the pathogenesis of RAS has stemmed from the observations that anti- TNF-α drugs such as thalidomide and pentoxifylline have been found to be effective in the treatment of RAS. Therefore, the present study was an attempt to measure the levels of salivary TNF-α in patients with RAS, which will reflect the local production of cytokines at the site of the disease. The aim was to evaluate the salivary levels of TNF-α in patients with recurrent aphthous stomatitis. Methods. The study comprised of 60 subjects, of whom 30 clinically proven RAS patients of either sex were selected as cases and 30 healthy, age- and gender- matched subjects were selected as controls. After taking informed consent, 5 mL of unstimulated saliva were collected from both the study and control group subjects. Determination of salivary TNF-α levels was carried out by Enzyme-Linked Immunosorbent Assay (ELISA) and expressed in pg/mL. Statistical analysis of the RAS and control groups was carried out using unpaired t-test. Gender-wise comparison of salivary TNF-α levels in the study and control groups was carried out using one-way ANOVA. Results. Mean salivary TNF-α levels were significantly higher in the RAS group compared to the control group (P<0.001). It was also revealed that the mean salivary TNF-α levels in females were significantly higher than in males in the study group (PP<0.05). Conclusion. It is fair to suggest that TNF-α plays a very important mediatory role in the pathogenesis of RAS and may play an important role in the search for a definitive treatment for the disease.

Exercise training in chronic heart failure: improving skeletal muscle O2 transport and utilization

PubMed Central

Hirai, Daniel M.; Musch, Timothy I.

2015-01-01

Chronic heart failure (CHF) impairs critical structural and functional components of the O2 transport pathway resulting in exercise intolerance and, consequently, reduced quality of life. In contrast, exercise training is capable of combating many of the CHF-induced impairments and enhancing the matching between skeletal muscle O2 delivery and utilization (Q̇mO2 and V̇mO2, respectively). The Q̇mO2/V̇mO2 ratio determines the microvascular O2 partial pressure (PmvO2), which represents the ultimate force driving blood-myocyte O2 flux (see Fig. 1). Improvements in perfusive and diffusive O2 conductances are essential to support faster rates of oxidative phosphorylation (reflected as faster V̇mO2 kinetics during transitions in metabolic demand) and reduce the reliance on anaerobic glycolysis and utilization of finite energy sources (thus lowering the magnitude of the O2 deficit) in trained CHF muscle. These adaptations contribute to attenuated muscle metabolic perturbations (e.g., changes in [PCr], [Cr], [ADP], and pH) and improved physical capacity (i.e., elevated critical power and maximal V̇mO2). Preservation of such plasticity in response to exercise training is crucial considering the dominant role of skeletal muscle dysfunction in the pathophysiology and increased morbidity/mortality of the CHF patient. This brief review focuses on the mechanistic bases for improved Q̇mO2/V̇mO2 matching (and enhanced PmvO2) with exercise training in CHF with both preserved and reduced ejection fraction (HFpEF and HFrEF, respectively). Specifically, O2 convection within the skeletal muscle microcirculation, O2 diffusion from the red blood cell to the mitochondria, and muscle metabolic control are particularly susceptive to exercise training adaptations in CHF. Alternatives to traditional whole body endurance exercise training programs such as small muscle mass and inspiratory muscle training, pharmacological treatment (e.g., sildenafil and pentoxifylline), and dietary nitrate supplementation are also presented in light of their therapeutic potential. Adaptations within the skeletal muscle O2 transport and utilization system underlie improvements in physical capacity and quality of life in CHF and thus take center stage in the therapeutic management of these patients. PMID:26320036

Topical Combinations to Treat Microvascular Dysfunction of Chronic Postischemia Pain

PubMed Central

Laferrière, André; Abaji, Rachid; Tsai, Cheng-Yu Mark; Ragavendran, J. Vaigunda; Coderre, Terence J.

2015-01-01

Background Growing evidence indicates that patients with complex regional pain syndrome (CRPS) exhibit tissue abnormalities caused by microvascular dysfunction in the blood vessels of skin, muscle and nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in an animal model of CRPS. We hypothesized that topical administration of either α2-adrenergic (α2A) receptor agonists or nitric oxide (NO) donors given to increase arterial blood flow, combined with either phosphatidic acid (PA) or phosphodiesterase (PDE) inhibitors to increase capillary blood flow, would effectively reduce allodynia and signs of microvascular dysfunction in the animal model of chronic pain. Methods Mechanical allodynia was induced in the hind paws of rats with chronic postischemia pain (CPIP). Allodynia was assessed before and after topical application of vehicle, single drugs or combinations of an α2A receptor agonist (apraclonidine) or an NO donor (linsidomine), with PA or PDE inhibitors (lisofylline, pentoxifylline). A topical combination of apraclonidine + lisofylline was also evaluated for its effects on a measure of microvascular function (post-occlusive reactive hyperemia) and tissue oxidative capacity (formazan production by tetrazolium reduction) in CPIP rats. Results Each of the single topical drugs produced significant dose-dependent antiallodynic effects compared to vehicle in CPIP rats (n = 30), and the antiallodynic dose-response curves of either PA or PDE inhibitors were shifted 5 to 10 fold to the left when combined with nonanalgesic doses of α2A receptor agonists or NO donors (n = 28). The potent antiallodynic effects of ipsilateral treatment with combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors, were not reproduced by the same treatment of the contralateral hindpaw (n = 28). Topical combinations produced antiallodynic effects lasting up to 6 h (n = 15), and were significantly enhanced by low dose systemic pregabalin in early, but not late, CPIP rats (n = 18). An antiallodynic topical combination of apraclonidine + lisofylline was also found to effectively relieve depressed post-occlusive reactive hyperemia in CPIP rats (n = 61), and to increase formazan production in postischemic tissues (skin and muscle) (n = 56). Conclusions The present results support the hypothesis that allodynia in an animal model of CRPS is effectively relieved by topical combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors. This suggests that topical treatments aimed at improving microvascular function by increasing both arterial and capillary blood flow produce effective analgesia for CRPS. PMID:24651238

Sperm preparation for ART

PubMed Central

Henkel, Ralf R; Schill, Wolf-Bernhard

2003-01-01

The onset of clinical assisted reproduction, a quarter of a century ago, required the isolation of motile spermatozoa. As the indication of assisted reproduction shifted from mere gynaecological indications to andrological indications during the years, this urged andrological research to understand the physiology of male germ cell better and develop more sophisticated techniques to separate functional spermatozoa from those that are immotile, have poor morphology or are not capable to fertilize oocytes. Initially, starting from simple washing of spermatozoa, separation techniques, based on different principles like migration, filtration or density gradient centrifugation evolved. The most simple and cheapest is the conventional swim-up procedure. A more sophisticated and most gentle migration method is migration-sedimentation. However, its yield is relatively small and the technique is therefore normally only limited to ejaculates with a high number of motile spermatozoa. Recently, however, the method was also successfully used to isolate spermatozoa for intracytoplasmic sperm injection (ICSI). Sperm separation methods that yield a higher number of motile spermatozoa are glass wool filtration or density gradient centrifugation with different media. Since Percoll® as a density medium was removed from the market in 1996 for clinical use in the human because of its risk of contamination with endotoxins, other media like IxaPrep®, Nycodenz, SilSelect®, PureSperm® or Isolate® were developed in order to replace Percoll®. Today, an array of different methods is available and the selection depends on the quality of the ejaculates, which also includes production of reactive oxygen species (ROS) by spermatozoa and leukocytes. Ejaculates with ROS production should not be separated by means of conventional swim-up, as this can severely damage the spermatozoa. In order to protect the male germ cells from the influence of ROS and to stimulate their motility to increase the yield, a number of substances can be added to the ejaculate or the separation medium. Caffeine, pentoxifylline and 2-deoxyadenosine are substances that were used to stimulate motility. Recent approaches to stimulate spermatozoa include bicarbonate, metal chelators or platelet-activating factor (PAF). While the use of PAF already resulted in pregnancies in intrauterine insemination, the suitability of the other substances for the clinical use still needs to be tested. Finally, the isolation of functional spermatozoa from highly viscous ejaculates is a special challenge and can be performed enzymatically to liquefy the ejaculate. The older method, by which the ejaculate is forcefully aspirated through a narrow-gauge needle, should be abandoned as it can severely damage spermatozoa, thus resulting in immotile sperm. PMID:14617368

Homozygosity for rs738409:G in PNPLA3 is associated with increased mortality following an episode of severe alcoholic hepatitis.

PubMed

Atkinson, Stephen R; Way, Michael J; McQuillin, Andrew; Morgan, Marsha Y; Thursz, Mark R

2017-07-01

Carriage of rs738409:G in PNPLA3 is associated with an increased risk of developing alcohol-related cirrhosis and has a significant negative effect on survival. Short-term mortality in patients with severe alcoholic hepatitis is high; drinking behaviour is a major determinant of outcome in survivors. The aim of this study was to determine whether carriage of rs738409:G has an additional detrimental effect on survival in this patient group. Genotyping was undertaken in 898 cases with severe alcoholic hepatitis, recruited through the UK Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial, and 1188 White British/Irish alcohol dependent controls with no liver injury, recruited via University College London. Subsequent drinking behaviour was classified, in cases surviving ≥90days, as abstinent or drinking. The relationship between rs738409 genotype, drinking behaviour and survival was explored. The frequency of rs738409:G was significantly higher in cases than controls (29.5% vs. 18.9%; p=2.15×10 -15 ; odds ratio 1.80 [95% confidence interval (CI) 1.55-2.08]). Case-mortality at days 28, 90 and 450 was 16%, 25% and 41% respectively. There was no association between rs738409:G and 28-day mortality. Mortality in the 90 to 450-day period was higher in survivors who subsequently resumed drinking (hazard ratio [HR] 2.77, 95% CI 1.79-4.29; p<0.0001) and in individuals homozygous for rs738409:G (HR 1.69, 95% CI 1.02-2.81, p=0.04). Homozygosity for rs738409:G in PNPLA3 confers significant additional risk of medium-term mortality in patients with severe alcoholic hepatitis. Rs738409 genotype may be taken into account when considering treatment options for these patients. Individuals misusing alcohol who carry a particular variant of the gene PNPLA3 are more at risk of developing severe alcoholic hepatitis, a condition with a poor chance of survival. The longer-term outcome in people with this condition who survive the initial illness is strongly influenced by their ability to remain abstinent from alcohol. However, carriers of this gene variant are less likely to survive even if they are able to stop drinking completely. Knowing if someone carries this gene variant could influence the way in which they are managed. Clinical trial numbers: EudraCT reference number: 2009-013897-42; ISRCTN reference number: ISRCTN88782125. EudraCT reference number: 2009-013897-42; ISRCTN reference number: ISRCTN88782125. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

A new approach combining different MRI methods to provide detailed view on swelling dynamics of xanthan tablets influencing drug release at different pH and ionic strength.

PubMed

Mikac, Ursa; Sepe, Ana; Kristl, Julijana; Baumgartner, Sasa

2010-08-03

The key element in drug release from hydrophilic matrix tablets is the gel layer that regulates the penetration of water and controls drug dissolution and diffusion. We have selected magnetic resonance imaging (MRI) as the method of choice for visualizing the dynamic processes occurring during the swelling of xanthan tablets in a variety of media. The aims were (i) to develop a new method using MRI for accurate determination of penetration, swelling and erosion fronts, (ii) to investigate the effects of pH and ionic strength on swelling, and (iii) to study the influence of structural changes in xanthan gel on drug release. Two dimensional (2D) MRI and one dimensional single point imaging (SPI) of swollen xanthan tablets were recorded, together with T(2) mapping. The border between dry and hydrated glassy xanthan-the penetration front-was determined from 1D SPI signal intensity profiles. The erosion front was obtained from signal intensity profiles of 2D MR images. The swelling front, where xanthan is transformed from a glassy to a rubbery state (gel formation), was determined from T(2) profiles. Further, the new combination of MRI methods for swelling front determination enables to explain the appearance of the unusual "bright front" observed on 2D MR images in tablets swollen in HCl pH 1.2 media, which represents the position of swelling front. All six media studied, differing in pH and ionic strength, penetrate through the whole tablet in 4h+/-0.3h, but formation of the gel layer is significantly delayed. Unexpectedly, the position of the swelling front was the same, independently of the different xanthan gel structures formed under different conditions of pH and ionic strength. The position of the erosion front, on the other hand, is strongly dependent on pH and ionic strength, as reflected in different thicknesses of the gel layers. The latter are seen to be the consequence of the different hydrodynamic radii of the xanthan molecules, which affect the drug release kinetics. The slowest release of pentoxifylline was observed in water where the thickest gel was formed, whereas the fastest release was observed in HCl pH 1.2, in which the gel layer was thinnest. Moreover, experiments simulating physiological conditions showed that changes of pH and ionic strength influence the xanthan gel structure relatively quickly, and consequently the drug release kinetics. It is therefore concluded that drug release is greatly influenced by changes in the xanthan molecular conformation, as reflected in changed thickness of the gel layer. A new method utilizing combination of SPI, multi-echo MRI and T(2) mapping eliminates the limitations of standard methods used in previous studies for determining moving fronts and improves current understanding of the dynamic processes involved in polymer swelling. Copyright (c) 2010 Elsevier B.V. All rights reserved.

[Sex, erectile dysfunction, and the heart: a growing problem].

PubMed

Görge, Günter; Flüchter, Stephan; Kirstein, Michael; Kunz, Thomas

2003-06-01

Erectile dysfunction (ED) is defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance. ED may also be an early sign of cardiovascular disease. The main risk factors for coronary heart disease (high LDL, smoking, hypertension, diabetes) and ED are the same. ED after the diagnosis of coronary artery disease or myocardial infarction is also common. Cardiac and metabolic expenditures during sexual intercourse will vary depending on the type of sexual activity. When oxygen uptake was measured in men, an average metabolic expenditure during stimulation and orgasm of 2.5 metabolic equivalents (METs) was found for woman-on-top coitus, and of 3.3 METs for man-on-top coitus (range 2.0-5.4 METs). However, coital death is rare, encompassing only 0.6% of all sudden death cases. A retrospective case-crossover study has shown that although sexual activity can trigger the onset of myocardial infarction, the relative risk in the 2 h after sexual activity was low (2.5; 95% confidence interval [CI] 1.7-3.7). Sexual activity was a likely contributor to the onset of myocardial infarction only 0.9% of the time. Regular exercise appears to prevent triggering. It has to be cautioned that these reassuring data should not be extrapolated to patients taking sildenafil, if they perform at higher cardiac and metabolic expenditures during coitus. The hemodynamic changes associated with sexual activity may be far greater with an unfamiliar partner, in unfamiliar settings, and after excessive eating and drinking. The Princeton Consensus Table for estimation of cardiovascular risk during sexual intercourse gives a first orientation regarding the question which patients can perform sex safely and which subgroup needs further diagnosis and treatment. PHOSPHODIESTERASE-5 INHIBITORS FOR ED TREATMENT: The introduction of sildenafil has been a valuable contribution to the treatment of ED. Sildenafil acts as a selective inhibitor of cyclic guanosine monophosphate-(cGMP-)specific phosphodiesterase type 5 (PDE 5), resulting in smooth muscle relaxation, vasodilation, and enhanced penile erection. Reported cardiovascular side effects in healthy males are headache, flushing, and < 10% decreases in systolic and diastolic blood pressures. Significant hypotension can be found in patients who are concurrently taking nitrates. On the basis of the pharmacokinetic profile of sildenafil, the co-administration of a nitrate within the first 24 h is likely to produce a severe, potentially lifethreatening hypotensive response and is therefore contraindicated. The risk of precipitating a cardiotoxic, hypotensive, or hemorrhagic event secondary to combining sildenafil (a PDE 5 inhibitor) with specific PDE 3 inhibitors such as milrinone and enoximone or with nonspecific PDE inhibitors such as theophylline and pentoxifylline is unlikely. Sildenafil is predominantly metabolized by both the P450 2C9 pathway and the P450 3A4 pathway. Thus, potent inhibitors of the P450 3A4 pathway may increase the plasma concentrations of sildenafil, like cimetidine, erythromycin, digitoxin, and CSE inhibitors (simvastatin, atorvastatin, etc.). A creatinine clearance < 30 ml/min also increases plasma levels of sildenafil. Sildenafil is safe in healthy subjects. In a postmarketing study on 6,527 males, no increase of cardiovascular events was found. However, in older males with coronary heart disease, the risk of sildenafil and the risk of physical exercise during sexual intercourse contribute both to fatal outcomes. Of 69 cases reported to the FDA, 46 patients might have had a cardiovascular event, and in twelve a possible interaction with nitrate use has been reported. Sildenafil is absolutely contraindicated in patients taking long-acting nitrates, those with severe aortic stenosis, and patients with hypertrophic obstructive cardiomyopathy (HOCM). No nitrates should be used within 24 h of sildenafil use. Caution is necessary in patients with a combination of antihypertensive medications, and in patients with cardiac insufficiency. A "pre-Viagra" treadmill test to assess for the presence of stress-induced ischemia can be helpful for both the patient and the physician. If the patient can achieve > or = 5 METs without demonstrating ischemia, the risk of ischemia during coitus is low. If severe hypotension occurs, aggressive fluid resuscitation is the first step, followed by administration of vasoactive drugs and, if necessary, by intraaortic balloon counterpulsation. If unstable angina or myocardial infarctions occurs after the use of sildenafil, the patient is treated according to the guidelines, but without nitrates. Sexual activity is a cornerstone of quality of life. However, giving the incidence of "occult" cardiovascular disease in patients with ED and the indications and contraindications of PDE 5 inhibitors in patients with cardiovascular diseases, all patients with ED must be evaluated by a cardiovascular specialist.

Clinically relevant enhancement of human sperm motility using compounds with reported phosphodiesterase inhibitor activity

PubMed Central

Tardif, Steve; Madamidola, Oladipo A.; Brown, Sean G.; Frame, Lorna; Lefièvre, Linda; Wyatt, Paul G.; Barratt, Christopher L.R.; Martins Da Silva, Sarah J.

2014-01-01

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 baseline motility. In ICSI samples, compounds #26, #37 and #38 were the most effective at significantly increasing total motility (88, 81 and 79% of samples, respectively) and progressive motility (94, 93 and 81% of samples, respectively). In conclusion, using a two-phased drug discovery screening approach including the examination of clinical samples, 3/43 compounds were identified as promising candidates for further study. LIMITATIONS, REASONS FOR CAUTION This is an in vitro study and caution must be taken when extrapolating the results. Data for patients were from one assessment and thus the robustness of responses needs to be established. The n values for ICSI samples were relatively small. WIDER IMPLICATIONS OF THE FINDINGS We have systematically screened and identified several compounds that have robust and effective stimulation (i.e. functional significance with longevity and no toxicity) of total and progressive motility under clinical conditions of treatment. These compounds could be clinical candidates with possibilities in terms of assisted reproductive technology options for current or future patients affected by asthenozoospermia or oligoasthenozoospermia. STUDY FUNDING/COMPETING INTEREST(S) This study was funded primarily by the MRC (DPFS) but with additional funding from the Wellcome Trust, Tenovus (Scotland), University of Dundee, NHS Tayside and Scottish Enterprise. The authors have no competing interests. A patent (#WO2013054111A1) has been published containing some of the information presented in this manuscript. PMID:25124668